14-100538178-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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEGAIN	NM_001385089.1	c.1630G>A	p.Gly544Arg	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.1630G>A	p.Gly544Arg	missense_variant	Exon 7 of 7	5	NM_001385089.1	ENSP00000451125.2

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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 31, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1573G>A (p.G525R) alteration is located in exon 6 (coding exon 6) of the BEGAIN gene. This alteration results from a G to A substitution at nucleotide position 1573, causing the glycine (G) at amino acid position 525 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.017	.;T;.;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.81	T;.;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	.;N;.;N
PhyloP100		0.0010
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.1	.;N;.;N
REVEL	Benign	0.033
Sift	Benign	0.16	.;T;.;T
Sift4G	Benign	0.38	.;T;.;T
Polyphen		0.0080	.;B;.;B
Vest4		0.080, 0.067
MutPred		0.37		.;Gain of catalytic residue at G521 (P = 0.0029);.;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;