Genetic Variant BEGAIN:p.Ala571Val (chr14-100538096-G-A) – 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.1712C>T(p.Ala571Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,428,834 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A571G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

BEGAIN
NM_001385089.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.34

Publications

0 publications found

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: 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=0.1619412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEGAIN	NM_001385089.1 link	c.1712C>T	p.Ala571Val	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>T	p.Ala571Val	missense_variant	Exon 7 of 7	5	NM_001385089.1	ENSP00000451125.2		G3V3A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1428834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

708236

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32390

American (AMR)

AF:

0.00

AC:

AN:

40630

Ashkenazi Jewish (ASJ)

AF:

0.00

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:

0.0000200

AC:

AN:

49878

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097522

Other (OTH)

AF:

0.00

AC:

AN:

58718

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.016

.;T;.;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.78

T;.;T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.6

.;L;.;L

PhyloP100

3.3

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.5

.;N;.;N

REVEL

Benign

0.036

Sift

Benign

0.078

.;T;.;T

Sift4G

Benign

0.43

.;T;.;T

Polyphen

0.084

.;B;.;B

Vest4

0.081

MutPred

0.24

.;Gain of catalytic residue at M550 (P = 0);.;Gain of catalytic residue at M550 (P = 0);

MVP

0.22

MPC

0.66

ClinPred

0.58

GERP RS

3.7

Varity_R

0.092

gMVP

0.34

Mutation Taster

=72/28

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over