chr14-100538178-C-T

Variant names:

• chr14-100538178-C-T
• rs1346352608
• NM_001385089.1:c.1630G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001385089.1(BEGAIN):​c.1630G>A​(p.Gly544Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,535,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: BEGAIN NM_001385089.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00100
• Publications: 0 publications found

Genes affected

BEGAIN (HGNC:24163): (brain enriched guanylate kinase associated) Predicted to be involved in regulation of postsynaptic neurotransmitter receptor activity. Predicted to act upstream of or within evoked excitatory postsynaptic potential. Predicted to be located in dendrite; nucleus; and presynapse. Predicted to be active in glutamatergic synapse and postsynapse. [provided by Alliance of Genome Resources, Apr 2022]

LOC124903382 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10410491).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385089.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEGAIN	NM_001385089.1	MANE Select	c.1630G>A	p.Gly544Arg	missense	Exon 7 of 7	NP_001372018.1	G3V3A2
	BEGAIN	NM_001385085.1		c.1720G>A	p.Gly574Arg	missense	Exon 8 of 8	NP_001372014.1
	BEGAIN	NM_001385086.1		c.1702G>A	p.Gly568Arg	missense	Exon 8 of 8	NP_001372015.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BEGAIN	ENST00000554140.3	TSL:5 MANE Select	c.1630G>A	p.Gly544Arg	missense	Exon 7 of 7	ENSP00000451125.2	G3V3A2
	BEGAIN	ENST00000355173.7	TSL:1	c.1573G>A	p.Gly525Arg	missense	Exon 7 of 7	ENSP00000347301.2	Q9BUH8
	BEGAIN	ENST00000557378.6	TSL:1	c.1573G>A	p.Gly525Arg	missense	Exon 6 of 6	ENSP00000450722.2	Q9BUH8

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152050 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1383220 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 682192

African (AFR) AF: 0.00 AC: 0 AN: 31190

American (AMR) AF: 0.00 AC: 0 AN: 35362

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22892

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36796

South Asian (SAS) AF: 0.00 AC: 0 AN: 76646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5108

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1076708

Other (OTH) AF: 0.00 AC: 0 AN: 57164

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152050 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74276

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67960

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N
PhyloP100		0.0010
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.033
Sift	Benign	0.16	T
Sift4G	Benign	0.38	T
Polyphen		0.0080	B
Vest4		0.080
MutPred		0.37		Gain of catalytic residue at G521 (P = 0.0029)
MVP		0.068
MPC		0.52
ClinPred		0.11	T
GERP RS		0.82
Varity_R		0.072
gMVP		0.13
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs1346352608; hg19: chr14-101004515; COSMIC: COSV100767004; COSMIC: COSV100767004;