14-102040310-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001376.5(DYNC1H1):c.11765C>T(p.Pro3922Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,614,182 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3922H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0049 ( 27 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 81 hom. )

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.91

Publications

8 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: Genomics England PanelApp, Orphanet, G2P
intellectual disability, autosomal dominant 13
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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: Orphanet, Labcorp Genetics (formerly Invitae)
autosomal dominant non-syndromic intellectual disability
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DYNC1H1 links:

ENSG00000293472 (HGNC:):

ENSG00000293472 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006579995).

BP6

Variant 14-102040310-C-T is Benign according to our data. Variant chr14-102040310-C-T is described in ClinVar as Benign. ClinVar VariationId is 312653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0049 (746/152296) while in subpopulation EAS AF = 0.0122 (63/5180). AF 95% confidence interval is 0.00976. There are 27 homozygotes in GnomAd4. There are 520 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 746 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001376.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	NM_001376.5	MANE Select	c.11765C>T	p.Pro3922Leu	missense	Exon 63 of 78	NP_001367.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.11765C>T	p.Pro3922Leu	missense	Exon 63 of 78	ENSP00000348965.4	Q14204
DYNC1H1	ENST00000681574.1		c.11765C>T	p.Pro3922Leu	missense	Exon 63 of 77	ENSP00000505523.1	A0A7P0T9C4
DYNC1H1	ENST00000679720.1		c.11765C>T	p.Pro3922Leu	missense	Exon 63 of 78	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes

AF:

0.00492

AC:

748

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0123

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0549

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00131

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00705

AC:

1774

AN:

251482

AF XY:

0.00659

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0116

Gnomad FIN exome

AF:

0.0582

Gnomad NFE exome

AF:

0.00210

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00293

AC:

4280

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

2045

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0166

AC:

660

AN:

39700

South Asian (SAS)

AF:

0.000858

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0529

AC:

2828

AN:

53412

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000471

AC:

524

AN:

1112012

Other (OTH)

AF:

0.00313

AC:

189

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

278

555

833

1110

1388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00490

AC:

746

AN:

152296

Hom.:

Cov.:

AF XY:

0.00698

AC XY:

520

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41554

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.0122

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0549

AC:

583

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00131

AC:

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

100

134

167

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:

0.00171

Hom.:

Bravo

AF:

0.000892

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00624

AC:

757

Asia WGS

AF:

0.00953

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Charcot-Marie-Tooth disease axonal type 2O (2)

not provided (2)

not specified (2)

Autosomal dominant cerebellar ataxia (1)

Charcot-Marie-Tooth disease (1)

DYNC1H1-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.66

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0066

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.83

PhyloP100

7.9

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.37

Sift

Benign

0.12

Polyphen

0.0010

Vest4

0.86

MVP

0.74

MPC

1.2

ClinPred

0.049

GERP RS

5.8

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.21

gMVP

0.79

Mutation Taster

=30/70

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over