chr2-214728679-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000465.4(BARD1):​c.2331C>G​(p.Ser777Arg) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S777N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

BARD1
NM_000465.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.140
Variant links:
Genes affected
BARD1 (HGNC:952): (BRCA1 associated RING domain 1) This gene encodes a protein which interacts with the N-terminal region of BRCA1. In addition to its ability to bind BRCA1 in vivo and in vitro, it shares homology with the 2 most conserved regions of BRCA1: the N-terminal RING motif and the C-terminal BRCT domain. The RING motif is a cysteine-rich sequence found in a variety of proteins that regulate cell growth, including the products of tumor suppressor genes and dominant protooncogenes. This protein also contains 3 tandem ankyrin repeats. The BARD1/BRCA1 interaction is disrupted by tumorigenic amino acid substitutions in BRCA1, implying that the formation of a stable complex between these proteins may be an essential aspect of BRCA1 tumor suppression. This protein may be the target of oncogenic mutations in breast or ovarian cancer. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0962497).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BARD1NM_000465.4 linkuse as main transcriptc.2331C>G p.Ser777Arg missense_variant 11/11 ENST00000260947.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BARD1ENST00000260947.9 linkuse as main transcriptc.2331C>G p.Ser777Arg missense_variant 11/111 NM_000465.4 P2Q99728-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsAug 20, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.068
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T;.;.;.;T;.
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.070
FATHMM_MKL
Benign
0.76
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;.
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.096
T;T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
1.4
L;.;.;.;.;.
MutationTaster
Benign
0.93
N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.1
N;.;.;.;.;.
REVEL
Benign
0.063
Sift
Uncertain
0.0060
D;.;.;.;.;.
Sift4G
Uncertain
0.0050
D;D;D;D;D;D
Polyphen
0.036
B;.;.;.;.;.
Vest4
0.13
MutPred
0.21
Gain of solvent accessibility (P = 0.0155);.;.;.;.;.;
MVP
0.84
MPC
0.10
ClinPred
0.35
T
GERP RS
2.7
Varity_R
0.12
gMVP
0.37

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-215593403; API