2-74378067-C-T

Position:

• chr2-74378067-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_004082.5(DCTN1):​c.212G>A​(p.Gly71Glu) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G71A) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DCTN1 NM_004082.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 U:1
• Conservation: PhyloP100: 7.81

Genes affected

DCTN1 (HGNC:2711): (dynactin subunit 1) This gene encodes the largest subunit of dynactin, a macromolecular complex consisting of 10 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein. Dynactin is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit interacts with dynein intermediate chain by its domains directly binding to dynein and binds to microtubules via a highly conserved glycine-rich cytoskeleton-associated protein (CAP-Gly) domain in its N-terminus. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause distal hereditary motor neuronopathy type VIIB (HMN7B) which is also known as distal spinal and bulbar muscular atrophy (dSBMA). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a strand (size 6) in uniprot entity DCTN1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_004082.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 2-74378067-C-T is Pathogenic according to our data. Variant chr2-74378067-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 21390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-74378067-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DCTN1	NM_004082.5	c.212G>A	p.Gly71Glu	missense_variant	2/32	ENST00000628224.3	NP_004073.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DCTN1	ENST00000628224.3	c.212G>A	p.Gly71Glu	missense_variant	2/32	5	NM_004082.5	ENSP00000487279	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Perry syndrome Pathogenic:3 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Sep 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostics Laboratory, National Institute of Medical Genomics	May 02, 2024	Gly71Glu variant in DCTN1 has been reported previously in individuals with Perry síndrome (PMID: 19136952, 24343258, 28625595, 32717578). This variant is absent in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 71 of the DCTN1 protein (p.Gly71Glu). Acording to Farrer et al, 2009 (PMID: 19136952) functional analysis on a similar variant, Gly71Arg, revealed a modest decrease in microtubule binding comparable to Gly59Ser. We perfomed an in silico analyisis of this variant: Glu71 modifies the electrostatic potential of the CAP-Gly domain. Using ACMG Guidelines 2015, this is a pathogenic variant. -

Neuronopathy, distal hereditary motor, type 7B;C1862939:Amyotrophic lateral sclerosis type 1;C1868594:Perry syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 15, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DCTN1 protein function. ClinVar contains an entry for this variant (Variation ID: 21390). This missense change has been observed in individuals with Perry syndrome (PMID: 19136952, 24343258, 28625595, 32717578). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 71 of the DCTN1 protein (p.Gly71Glu). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

DCTN1: PP1:Strong, PM1, PM2, PM5, PS4:Moderate, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;D;.;D;.;.;D;D;.;D;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;.;D;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H;H;.;.;.;H;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.3	D;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.;.;D;.;D;D;D
Polyphen		0.98	D;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.99
MutPred		0.98		Gain of methylation at K66 (P = 0.0633);Gain of methylation at K66 (P = 0.0633);.;.;.;Gain of methylation at K66 (P = 0.0633);.;.;.;.;.;.;.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs67586389; hg19: chr2-74605194;