chr14-101964737-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001376.5(DYNC1H1):c.46T>C(p.Leu16Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00379 in 1,596,858 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0055 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 117 hom. )

Consequence

DYNC1H1
NM_001376.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.820

Publications

5 publications found

Variant links:

Genes affected

DYNC1H1 (HGNC:2961): (dynein cytoplasmic 1 heavy chain 1) Dyneins are a group of microtubule-activated ATPases that function as molecular motors. They are divided into two subgroups of axonemal and cytoplasmic dyneins. The cytoplasmic dyneins function in intracellular motility, including retrograde axonal transport, protein sorting, organelle movement, and spindle dynamics. Molecules of conventional cytoplasmic dynein are comprised of 2 heavy chain polypeptides and a number of intermediate and light chains.This gene encodes a member of the cytoplasmic dynein heavy chain family. [provided by RefSeq, Oct 2008]

DYNC1H1 Gene-Disease associations (from GenCC):

autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
intellectual disability, autosomal dominant 13
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
neuronopathy, distal hereditary motor
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Charcot-Marie-Tooth disease axonal type 2O
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DYNC1H1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 14-101964737-T-C is Benign according to our data. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-101964737-T-C is described in CliVar as Benign. Clinvar id is 128938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.82 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00551 (837/151990) while in subpopulation EAS AF = 0.0365 (188/5146). AF 95% confidence interval is 0.0323. There are 17 homozygotes in GnomAd4. There are 451 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 837 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 link	c.46T>C	p.Leu16Leu	synonymous_variant	Exon 1 of 78	ENST00000360184.10	NP_001367.2	Q14204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10 link	c.46T>C	p.Leu16Leu	synonymous_variant	Exon 1 of 78	1	NM_001376.5	ENSP00000348965.4		Q14204

Frequencies

GnomAD3 genomes

AF:

0.00543

AC:

824

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00177

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0291

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0361

Gnomad SAS

AF:

0.0170

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00480

GnomAD2 exomes

AF:

0.0122

AC:

2653

AN:

216820

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.000980

Gnomad AMR exome

AF:

0.0495

Gnomad ASJ exome

AF:

0.000847

Gnomad EAS exome

AF:

0.0327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000298

Gnomad OTH exome

AF:

0.00669

GnomAD4 exome

AF:

0.00361

AC:

5209

AN:

1444868

Hom.:

117

Cov.:

AF XY:

0.00358

AC XY:

2569

AN XY:

718432

show subpopulations

African (AFR)

AF:

0.00141

AC:

AN:

33254

American (AMR)

AF:

0.0461

AC:

2018

AN:

43728

Ashkenazi Jewish (ASJ)

AF:

0.000965

AC:

AN:

25912

East Asian (EAS)

AF:

0.0366

AC:

1433

AN:

39136

South Asian (SAS)

AF:

0.0137

AC:

1168

AN:

85118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44424

Middle Eastern (MID)

AF:

0.00749

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000190

AC:

211

AN:

1107738

Other (OTH)

AF:

0.00441

AC:

264

AN:

59816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

291

581

872

1162

1453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00551

AC:

837

AN:

151990

Hom.:

Cov.:

AF XY:

0.00607

AC XY:

451

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

41468

American (AMR)

AF:

0.0294

AC:

450

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.0365

AC:

188

AN:

5146

South Asian (SAS)

AF:

0.0174

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

67930

Other (OTH)

AF:

0.00475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00727

Asia WGS

AF:

0.0250

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 07, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Charcot-Marie-Tooth disease axonal type 2O

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 21, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Autosomal dominant cerebellar ataxia

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.66

PhyloP100

0.82

PromoterAI

0.010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over