14-102050136-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_001376.5(DYNC1H1):c.13750G>T(p.Ala4584Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4584T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.57

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:

ENSG00000293472 (HGNC:):

ENSG00000293472 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 (MetaRNN=0.09325421).

BP6

Variant 14-102050136-G-T is Benign according to our data. Variant chr14-102050136-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3606222.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000412 (6/1457042) while in subpopulation SAS AF = 0.0000696 (6/86250). AF 95% confidence interval is 0.00003. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DYNC1H1	NM_001376.5	MANE Select	c.13750G>T	p.Ala4584Ser	missense	Exon 77 of 78	NP_001367.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DYNC1H1	ENST00000360184.10	TSL:1 MANE Select	c.13750G>T	p.Ala4584Ser	missense	Exon 77 of 78	ENSP00000348965.4
DYNC1H1	ENST00000681574.1		c.13750G>T	p.Ala4584Ser	missense	Exon 77 of 77	ENSP00000505523.1
DYNC1H1	ENST00000679720.1		c.13750G>T	p.Ala4584Ser	missense	Exon 77 of 78	ENSP00000505938.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251462

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457042

Hom.:

Cov.:

AF XY:

0.00000828

AC XY:

AN XY:

724812

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

36972

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111036

Other (OTH)

AF:

0.00

AC:

AN:

60114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2O

Benign:1

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.77

CADD

Benign

9.8

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.069

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

M_CAP

Benign

0.0060

MetaRNN

Benign

0.093

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.17

PhyloP100

1.6

PrimateAI

Benign

0.22

PROVEAN

Benign

0.41

REVEL

Benign

0.052

Sift

Benign

0.71

Polyphen

0.0010

Vest4

0.16

MutPred

0.58

Gain of relative solvent accessibility (P = 0.0215)

MVP

0.13

MPC

0.85

ClinPred

0.021

GERP RS

0.88

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.094

gMVP

0.24

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over