chr14-102012445-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong

The NM_001376.5(DYNC1H1):​c.6989G>A​(p.Gly2330Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

DYNC1H1
NM_001376.5 missense

Scores

16
1
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 10.0
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DYNC1H1. . Gene score misZ 10.967 (greater than the threshold 3.09). Trascript score misZ 16.053 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, neuronopathy, distal hereditary motor, intellectual disability, autosomal dominant 13, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease axonal type 2O.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.955
PP5
Variant 14-102012445-G-A is Pathogenic according to our data. Variant chr14-102012445-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DYNC1H1NM_001376.5 linkuse as main transcriptc.6989G>A p.Gly2330Glu missense_variant 34/78 ENST00000360184.10 NP_001367.2 Q14204

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DYNC1H1ENST00000360184.10 linkuse as main transcriptc.6989G>A p.Gly2330Glu missense_variant 34/781 NM_001376.5 ENSP00000348965.4 Q14204

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 17, 2017- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 27, 2024Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18466635, 25512093, 26100331, 25609763, 38848546, 37596007) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Pathogenic
0.97
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.4
H
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-7.8
D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.85
MutPred
0.71
Gain of solvent accessibility (P = 0.005);
MVP
0.96
MPC
2.7
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.97
gMVP
0.99

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555410010; hg19: chr14-102478782; API