2-214807822-G-T

Variant names:

• chr2-214807822-G-T
• rs6435862
• NM_000465.4:c.158+1590C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000465.4(BARD1):​c.158+1590C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.747 in 152,178 control chromosomes in the GnomAD database, including 42,464 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 0.75 (42464 hom., cov: 33)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 69 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 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+1590C>A		intron	N/A	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.158+1590C>A		intron	N/A	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.158+1590C>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+1590C>A		intron	N/A	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.158+1590C>A		intron	N/A	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.158+1590C>A		intron	N/A	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.746 AC: 113501 AN: 152060 Hom.: 42413 Cov.: 33

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.724

Gnomad EAS AF: 0.849

Gnomad SAS AF: 0.743

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.737

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

GnomAD4 genome AF: 0.747 AC: 113608 AN: 152178 Hom.: 42464 Cov.: 33 AF XY: 0.750 AC XY: 55811 AN XY: 74394

African (AFR) AF: 0.734 AC: 30466 AN: 41502

American (AMR) AF: 0.815 AC: 12459 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 2511 AN: 3470

East Asian (EAS) AF: 0.849 AC: 4397 AN: 5176

South Asian (SAS) AF: 0.744 AC: 3593 AN: 4828

European-Finnish (FIN) AF: 0.765 AC: 8097 AN: 10580

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49629 AN: 68012

Other (OTH) AF: 0.740 AC: 1564 AN: 2114

Alfa AF: 0.733 Hom.: 171316

Bravo AF: 0.750

Asia WGS AF: 0.790 AC: 2743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.83
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6435862; hg19: chr2-215672546;