dbSNP rs772070566: DYNC1H1:p.Ala54Glu (chr14-101964852-C-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PM2PP2BP4_ModerateBP6_ModerateBS2

The NM_001376.5(DYNC1H1):c.161C>A(p.Ala54Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000346 in 1,445,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

DYNC1H1
NM_001376.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.48

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the DYNC1H1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 122 curated pathogenic missense variants (we use a threshold of 10). The gene has 287 curated benign missense variants. Gene score misZ: 10.967 (above the threshold of 3.09). Trascript score misZ: 16.053 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.16998452).

BP6

Variant 14-101964852-C-A is Benign according to our data. Variant chr14-101964852-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 3636108.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DYNC1H1	NM_001376.5 link	c.161C>A	p.Ala54Glu	missense_variant	Exon 1 of 78	ENST00000360184.10	NP_001367.2	Q14204

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DYNC1H1	ENST00000360184.10 link	c.161C>A	p.Ala54Glu	missense_variant	Exon 1 of 78	1	NM_001376.5	ENSP00000348965.4		Q14204

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000935

AC:

AN:

213952

Hom.:

AF XY:

0.00000852

AC XY:

AN XY:

117386

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 SAS exome

AF:

0.0000708

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000346

AC:

AN:

1445848

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717862

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000837

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

Mar 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.91

REVEL

Benign

0.071

Sift

Benign

0.17

Polyphen

0.020

Vest4

0.34

MutPred

0.18

Gain of solvent accessibility (P = 0.08);

MVP

0.35

MPC

1.4

ClinPred

0.31

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.68

gMVP

0.60

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over