2-214757506-A-T

Variant names:

• chr2-214757506-A-T
• rs10190829
• NM_000465.4:c.1569-4951T>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.1569-4951T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 151,868 control chromosomes in the GnomAD database, including 15,038 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 0.44 (15038 hom., cov: 31)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.109
• Publications: 2 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):

• breast cancer

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

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.485 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.1569-4951T>A		intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.1512-4951T>A		intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.216-4951T>A		intron	N/A	NP_001269474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.1569-4951T>A		intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.1512-4951T>A		intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.1161-4951T>A		intron	N/A	ENSP00000484976.2

Frequencies

GnomAD3 genomes AF: 0.444 AC: 67366 AN: 151748 Hom.: 15016 Cov.: 31

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.419

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.458

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

GnomAD4 genome AF: 0.444 AC: 67416 AN: 151868 Hom.: 15038 Cov.: 31 AF XY: 0.449 AC XY: 33305 AN XY: 74216

African (AFR) AF: 0.480 AC: 19845 AN: 41386

American (AMR) AF: 0.395 AC: 6033 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1515 AN: 3472

East Asian (EAS) AF: 0.419 AC: 2163 AN: 5162

South Asian (SAS) AF: 0.502 AC: 2413 AN: 4808

European-Finnish (FIN) AF: 0.489 AC: 5146 AN: 10514

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28833 AN: 67946

Other (OTH) AF: 0.457 AC: 960 AN: 2100

Alfa AF: 0.300 Hom.: 740

Bravo AF: 0.431

Asia WGS AF: 0.455 AC: 1578 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.74
DANN	Benign	0.31
PhyloP100		-0.11
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: rs10190829; hg19: chr2-215622230;