14-100538352-G-C

Variant names:

• chr14-100538352-G-C
• NM_001385089.1:c.1456C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001385089.1(BEGAIN):​c.1456C>G​(p.Leu486Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BEGAIN NM_001385089.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3092265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEGAIN	NM_001385089.1	c.1456C>G	p.Leu486Val	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.1456C>G	p.Leu486Val	missense_variant	Exon 7 of 7	5	NM_001385089.1	ENSP00000451125.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1399C>G (p.L467V) alteration is located in exon 6 (coding exon 6) of the BEGAIN gene. This alteration results from a C to G substitution at nucleotide position 1399, causing the leucine (L) at amino acid position 467 to be replaced by a valine (V). 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	0.087
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.022	.;T;.;T
Eigen	Benign	-0.023
Eigen_PC	Benign	-0.0039
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T;.;T;T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.9	.;L;.;L
PhyloP100		2.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.68	.;N;.;N
REVEL	Benign	0.054
Sift	Uncertain	0.0070	.;D;.;D
Sift4G	Benign	0.064	.;T;.;T
Polyphen		0.59	.;P;.;P
Vest4		0.036, 0.044
MutPred		0.22		.;Gain of catalytic residue at Y468 (P = 0.0028);.;Gain of catalytic residue at Y468 (P = 0.0028);
MVP		0.20
MPC		0.75
ClinPred		0.18	T
GERP RS		2.7
Varity_R		0.078
gMVP		0.20
Mutation Taster		=96/4	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

Publications

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Other links and lift over

hg19: chr14-101004689;