14-100538200-C-A

Variant names:

• chr14-100538200-C-A
• rs553312951
• NM_001385089.1:c.1608G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001385089.1(BEGAIN):​c.1608G>T​(p.Glu536Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000624 in 1,554,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000062 (1 hom.)
• Consequence: BEGAIN NM_001385089.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.148
• Publications: 3 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01943037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEGAIN	NM_001385089.1	c.1608G>T	p.Glu536Asp	missense_variant	Exon 7 of 7	ENST00000554140.3	NP_001372018.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEGAIN	ENST00000554140.3	c.1608G>T	p.Glu536Asp	missense_variant	Exon 7 of 7	5	NM_001385089.1	ENSP00000451125.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000132 AC: 21 AN: 159666 AF XY: 0.000157

Gnomad AFR exome AF: 0.000542

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000227

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000621 AC: 87 AN: 1401910 Hom.: 1 Cov.: 31 AF XY: 0.0000821 AC XY: 57 AN XY: 693886

African (AFR) AF: 0.000221 AC: 7 AN: 31728

American (AMR) AF: 0.00 AC: 0 AN: 37692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23980

East Asian (EAS) AF: 0.000452 AC: 17 AN: 37614

South Asian (SAS) AF: 0.000762 AC: 61 AN: 80074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5450

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086736

Other (OTH) AF: 0.0000345 AC: 2 AN: 58030

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74408

African (AFR) AF: 0.000168 AC: 7 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000102 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1551G>T (p.E517D) alteration is located in exon 6 (coding exon 6) of the BEGAIN gene. This alteration results from a G to T substitution at nucleotide position 1551, causing the glutamic acid (E) at amino acid position 517 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	3.4
DANN	Benign	0.95
DEOGEN2	Benign	0.012	.;T;.;T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.61	T;.;T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.019	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	.;N;.;N
PhyloP100		0.15
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.50	.;N;.;N
REVEL	Benign	0.075
Sift	Benign	0.74	.;T;.;T
Sift4G	Benign	0.36	.;T;.;T
Polyphen		0.0	.;B;.;B
Vest4		0.030, 0.048
MutPred		0.11		.;Gain of catalytic residue at G519 (P = 0.001);.;Gain of catalytic residue at G519 (P = 0.001);
MVP		0.16
MPC		0.39
ClinPred		0.010	T
GERP RS		-0.28
Varity_R		0.039
gMVP		0.081
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: rs553312951; hg19: chr14-101004537; COSMIC: COSV100767059; COSMIC: COSV100767059;