dbSNP rs12161908: DYNC1H1:c.2719-130G>C (chr14-101988573-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001376.5(DYNC1H1):c.2719-130G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,173,818 control chromosomes in the GnomAD database, including 119 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0059 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 102 hom. )

Consequence

DYNC1H1
NM_001376.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.228

Publications

1 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0059 (899/152294) while in subpopulation EAS AF = 0.0367 (190/5182). AF 95% confidence interval is 0.0324. There are 17 homozygotes in GnomAd4. There are 481 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 899 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 link	c.2719-130G>C		intron_variant	Intron 9 of 77	ENST00000360184.10	NP_001367.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10 link	c.2719-130G>C		intron_variant	Intron 9 of 77	1	NM_001376.5	ENSP00000348965.4

Frequencies

GnomAD3 genomes

AF:

0.00583

AC:

887

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0292

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.0362

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00526

GnomAD4 exome

AF:

0.00441

AC:

4508

AN:

1021524

Hom.:

102

AF XY:

0.00440

AC XY:

2288

AN XY:

519600

show subpopulations

African (AFR)

AF:

0.00283

AC:

AN:

24412

American (AMR)

AF:

0.0462

AC:

1642

AN:

35554

Ashkenazi Jewish (ASJ)

AF:

0.000975

AC:

AN:

22556

East Asian (EAS)

AF:

0.0373

AC:

1303

AN:

34898

South Asian (SAS)

AF:

0.0146

AC:

1058

AN:

72688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37022

Middle Eastern (MID)

AF:

0.00835

AC:

AN:

4790

European-Non Finnish (NFE)

AF:

0.000218

AC:

162

AN:

744130

Other (OTH)

AF:

0.00466

AC:

212

AN:

45474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

223

447

670

894

1117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.00590

AC:

899

AN:

152294

Hom.:

Cov.:

AF XY:

0.00646

AC XY:

481

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00301

AC:

125

AN:

41552

American (AMR)

AF:

0.0295

AC:

452

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.0367

AC:

190

AN:

5182

South Asian (SAS)

AF:

0.0191

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68030

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

137

183

229

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00281

Hom.:

Bravo

AF:

0.00769

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.47

(source)

DANN

Benign

0.39

PhyloP100

-0.23

Mutation Taster

=100/0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over