Genetic Variant BEGAIN:p.Ala571Gly (chr14-100538096-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001385089.1(BEGAIN):c.1712C>G(p.Ala571Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000987 in 1,580,926 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

BEGAIN
NM_001385089.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.34

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1143924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEGAIN	NM_001385089.1 link	c.1712C>G	p.Ala571Gly	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.1712C>G	p.Ala571Gly	missense_variant	Exon 7 of 7	5	NM_001385089.1	ENSP00000451125.2		G3V3A2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000121

AC:

AN:

206236

AF XY:

0.0000971

show subpopulations

Gnomad AFR exome

AF:

0.0000744

Gnomad AMR exome

AF:

0.000134

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000219

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

145

AN:

1428834

Hom.:

Cov.:

AF XY:

0.000102

AC XY:

AN XY:

708236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32390

American (AMR)

AF:

0.0000984

AC:

AN:

40630

Ashkenazi Jewish (ASJ)

AF:

0.0000415

AC:

AN:

24092

East Asian (EAS)

AF:

0.00

AC:

AN:

39164

South Asian (SAS)

AF:

0.00

AC:

AN:

81682

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4758

European-Non Finnish (NFE)

AF:

0.000122

AC:

134

AN:

1097522

Other (OTH)

AF:

0.000102

AC:

AN:

58718

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41424

American (AMR)

AF:

0.0000654

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67976

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1655C>G (p.A552G) 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 1655, causing the alanine (A) at amino acid position 552 to be replaced by a glycine (G). 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

0.079

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.015

.;T;.;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.70

T;.;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.4

.;L;.;L

PhyloP100

3.3

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.90

.;N;.;N

REVEL

Benign

0.070

Sift

Benign

0.088

.;T;.;T

Sift4G

Benign

0.21

.;T;.;T

Polyphen

0.021

.;B;.;B

Vest4

0.082, 0.087

MVP

0.22

MPC

0.49

ClinPred

0.026

GERP RS

3.7

Varity_R

0.12

gMVP

0.25

Mutation Taster

=74/26

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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14-100538096-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over