10-127175533-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001039762.3(INSYN2A):c.863G>A(p.Arg288Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,610,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: INSYN2A NM_001039762.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.429

Genes affected

INSYN2A (HGNC:33859): (inhibitory synaptic factor 2A) Predicted to be involved in inhibitory postsynaptic potential. Predicted to be active in postsynaptic density. [provided by Alliance of Genome Resources, Apr 2022]

DOCK1 (HGNC:2987): (dedicator of cytokinesis 1) This gene encodes a member of the dedicator of cytokinesis protein family. Dedicator of cytokinesis proteins act as guanine nucleotide exchange factors for small Rho family G proteins. The encoded protein regulates the small GTPase Rac, thereby influencing several biological processes, including phagocytosis and cell migration. Overexpression of this gene has also been associated with certain cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.020200819).
• BP6: Variant 10-127175533-C-T is Benign according to our data. Variant chr10-127175533-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3109987.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INSYN2A	NM_001039762.3	c.863G>A	p.Arg288Gln	missense_variant	4/6	ENST00000522781.6
DOCK1	NM_001290223.2	c.2847+47769C>T		intron_variant		ENST00000623213.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INSYN2A	ENST00000522781.6	c.863G>A	p.Arg288Gln	missense_variant	4/6	2	NM_001039762.3	P1
DOCK1	ENST00000623213.2	c.2847+47769C>T		intron_variant		1	NM_001290223.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000568 AC: 14 AN: 246396 Hom.: 0 AF XY: 0.0000448 AC XY: 6 AN XY: 133834

Gnomad AFR exome AF: 0.000572

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1457948 Hom.: 0 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 725466

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74324

Gnomad4 AFR AF: 0.000555

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000249

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.22
Dann	Benign	0.90
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.61	T;T;.
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.27	T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.032	.;B;.
Vest4		0.11
MVP		0.068
MPC		0.15
ClinPred		0.022	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.020
gMVP		0.14

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

Other links and lift over

dbSNP: rs376061425; hg19: chr10-128973797;