2-214809213-C-T

Variant names:

• chr2-214809213-C-T
• rs13021937
• NM_000465.4:c.158+199G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000465.4(BARD1):​c.158+199G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.738 in 152,126 control chromosomes in the GnomAD database, including 41,444 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.74 (41444 hom., cov: 33)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.480
• Publications: 18 publications found

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]

BARD1 Gene-Disease associations (from GenCC):

• BARD1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-214809213-C-T is Benign according to our data. Variant chr2-214809213-C-T is described in ClinVar as Benign. ClinVar VariationId is 1286148.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000465.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.158+199G>A		intron	N/A	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.158+199G>A		intron	N/A	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.158+199G>A		intron	N/A	NP_001269474.1	C9IYG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.158+199G>A		intron	N/A	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.158+199G>A		intron	N/A	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.158+199G>A		intron	N/A	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112073 AN: 152006 Hom.: 41380 Cov.: 33

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.763

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.721

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

GnomAD4 genome AF: 0.738 AC: 112195 AN: 152126 Hom.: 41444 Cov.: 33 AF XY: 0.740 AC XY: 55015 AN XY: 74352

African (AFR) AF: 0.760 AC: 31534 AN: 41498

American (AMR) AF: 0.784 AC: 11990 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2501 AN: 3466

East Asian (EAS) AF: 0.805 AC: 4162 AN: 5170

South Asian (SAS) AF: 0.669 AC: 3224 AN: 4820

European-Finnish (FIN) AF: 0.763 AC: 8073 AN: 10584

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.711 AC: 48352 AN: 67992

Other (OTH) AF: 0.724 AC: 1524 AN: 2104

Alfa AF: 0.735 Hom.: 5130

Bravo AF: 0.741

Asia WGS AF: 0.742 AC: 2578 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.3
DANN	Benign	0.71
PhyloP100		-0.48
PromoterAI		-0.077	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs13021937; hg19: chr2-215673937;