rs17541165

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001376.5(DYNC1H1):c.7458G>T(p.Leu2486Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,610,246 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2486L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 12 hom. )

Consequence

DYNC1H1
NM_001376.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.27

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 14-102016071-G-T is Benign according to our data. Variant chr14-102016071-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.27 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00144 (220/152344) while in subpopulation SAS AF = 0.00662 (32/4832). AF 95% confidence interval is 0.00482. There are 1 homozygotes in GnomAd4. There are 114 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 220 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.7458G>T	p.Leu2486Leu	synonymous	Exon 36 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.7458G>T	p.Leu2486Leu	synonymous	Exon 36 of 78	ENSP00000348965.4	Q14204
DYNC1H1	ENST00000681574.1		c.7458G>T	p.Leu2486Leu	synonymous	Exon 36 of 77	ENSP00000505523.1	A0A7P0T9C4
DYNC1H1	ENST00000679720.1		c.7458G>T	p.Leu2486Leu	synonymous	Exon 36 of 78	ENSP00000505938.1	A0A7P0TA13

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00208

AC:

506

AN:

242694

AF XY:

0.00263

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.000649

Gnomad ASJ exome

AF:

0.000303

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000149

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.00200

GnomAD4 exome

AF:

0.00197

AC:

2868

AN:

1457902

Hom.:

Cov.:

AF XY:

0.00219

AC XY:

1587

AN XY:

724962

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

33358

American (AMR)

AF:

0.000880

AC:

AN:

44296

Ashkenazi Jewish (ASJ)

AF:

0.000154

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.00853

AC:

730

AN:

85620

European-Finnish (FIN)

AF:

0.0000572

AC:

AN:

52414

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00176

AC:

1953

AN:

1110622

Other (OTH)

AF:

0.00187

AC:

113

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

182

364

546

728

910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<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:

0.00144

AC:

220

AN:

152344

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

114

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41580

American (AMR)

AF:

0.00379

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00662

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

68032

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00138

Hom.:

Bravo

AF:

0.00144

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Charcot-Marie-Tooth disease axonal type 2O (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

BayesDel_noAF

Benign

-0.45

CADD

Benign

8.0

(source)

DANN

Benign

0.65

PhyloP100

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=98/2

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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