Genetic Variant BEGAIN:p.Gly472Arg (chr14-100538394-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001385089.1(BEGAIN):c.1414G>C(p.Gly472Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,377,922 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

BEGAIN
NM_001385089.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.744

Variant links:

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]

BEGAIN links:

LOC124903382 (HGNC:):

LOC124903382 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.11107612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEGAIN	NM_001385089.1 link	c.1414G>C	p.Gly472Arg	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 link	c.1414G>C	p.Gly472Arg	missense_variant	Exon 7 of 7	5	NM_001385089.1	ENSP00000451125.2		G3V3A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000635

AC:

AN:

157418

AF XY:

0.0000114

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000290

AC:

AN:

1377922

Hom.:

Cov.:

AF XY:

0.00000442

AC XY:

AN XY:

679446

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30002

American (AMR)

AF:

0.00

AC:

AN:

32154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21154

East Asian (EAS)

AF:

0.00

AC:

AN:

37996

South Asian (SAS)

AF:

0.0000135

AC:

AN:

74328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5454

European-Non Finnish (NFE)

AF:

0.00000279

AC:

AN:

1076934

Other (OTH)

AF:

0.00

AC:

AN:

56722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1357G>C (p.G453R) alteration is located in exon 6 (coding exon 6) of the BEGAIN gene. This alteration results from a G to C substitution at nucleotide position 1357, causing the glycine (G) at amino acid position 453 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

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

8.5

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.0097

.;T;.;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.74

T;.;T;T

M_CAP

Benign

0.058

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

.;L;.;L

PhyloP100

0.74

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.0

.;N;.;N

REVEL

Benign

0.018

Sift

Benign

0.20

.;T;.;T

Sift4G

Benign

0.15

.;T;.;T

Polyphen

0.0010

.;B;.;B

Vest4

0.085, 0.11

MutPred

0.29

.;Gain of catalytic residue at Y449 (P = 0.0017);.;Gain of catalytic residue at Y449 (P = 0.0017);

MVP

0.14

MPC

0.53

ClinPred

0.035

GERP RS

1.0

Varity_R

0.055

gMVP

0.15

Mutation Taster

=95/5

polymorphism

(source)

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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14-100538394-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over