2-214768739-A-G

Position:

• chr2-214768739-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000465.4(BARD1):​c.1395+493T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 152,122 control chromosomes in the GnomAD database, including 44,243 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.76 (44243 hom., cov: 34)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.306

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.1395+493T>C		intron_variant		ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.1395+493T>C		intron_variant		1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114863 AN: 152004 Hom.: 44221 Cov.: 34

Gnomad AFR AF: 0.599

Gnomad AMI AF: 0.757

Gnomad AMR AF: 0.754

Gnomad ASJ AF: 0.831

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.839

Gnomad FIN AF: 0.900

Gnomad MID AF: 0.759

Gnomad NFE AF: 0.805

Gnomad OTH AF: 0.736

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.755 AC: 114928 AN: 152122 Hom.: 44243 Cov.: 34 AF XY: 0.761 AC XY: 56582 AN XY: 74366

Gnomad4 AFR AF: 0.599

Gnomad4 AMR AF: 0.754

Gnomad4 ASJ AF: 0.831

Gnomad4 EAS AF: 0.949

Gnomad4 SAS AF: 0.839

Gnomad4 FIN AF: 0.900

Gnomad4 NFE AF: 0.805

Gnomad4 OTH AF: 0.739

Alfa AF: 0.797 Hom.: 90746

Bravo AF: 0.738

Asia WGS AF: 0.861 AC: 2993 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.87

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

LitVar

Other links and lift over

dbSNP: rs4234006; hg19: chr2-215633463;