2-214768739-A-G

Variant names:

• chr2-214768739-A-G
• rs4234006
• NM_000465.4:c.1395+493T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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=-0.75).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 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.1395+493T>C		intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.1338+493T>C		intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.216-16184T>C		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.1395+493T>C		intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.1338+493T>C		intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.987+493T>C		intron	N/A	ENSP00000484976.2

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

African (AFR) AF: 0.599 AC: 24832 AN: 41456

American (AMR) AF: 0.754 AC: 11515 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 2884 AN: 3470

East Asian (EAS) AF: 0.949 AC: 4920 AN: 5184

South Asian (SAS) AF: 0.839 AC: 4041 AN: 4818

European-Finnish (FIN) AF: 0.900 AC: 9544 AN: 10608

Middle Eastern (MID) AF: 0.765 AC: 225 AN: 294

European-Non Finnish (NFE) AF: 0.805 AC: 54717 AN: 67992

Other (OTH) AF: 0.739 AC: 1561 AN: 2112

Alfa AF: 0.788 Hom.: 149242

Bravo AF: 0.738

Asia WGS AF: 0.861 AC: 2993 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.87
PhyloP100		0.31
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: rs4234006; hg19: chr2-215633463;