chr2-214792457-T-C

Variant names:

• chr2-214792457-T-C
• rs199846428
• NM_000465.4:c.216-12A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000465.4(BARD1):​c.216-12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000747 in 1,338,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 29)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: BARD1 NM_000465.4 intron
• Scores: Splicing: ADA: 0.9972
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.528
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.216-12A>G		intron	N/A	NP_000456.2
	BARD1	NM_001282543.2		c.159-12A>G		intron	N/A	NP_001269472.1
	BARD1	NM_001282545.2		c.215+4604A>G		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.216-12A>G		intron	N/A	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.159-12A>G		intron	N/A	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.216-12A>G		intron	N/A	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 7.47e-7 AC: 1 AN: 1338916 Hom.: 0 Cov.: 33 AF XY: 0.00000151 AC XY: 1 AN XY: 662078

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27640

American (AMR) AF: 0.00 AC: 0 AN: 26878

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23054

East Asian (EAS) AF: 0.00 AC: 0 AN: 33262

South Asian (SAS) AF: 0.00 AC: 0 AN: 69288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4454

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1059660

Other (OTH) AF: 0.0000182 AC: 1 AN: 54946

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	18
DANN	Benign	0.61
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.99		Position offset: -1
DS_AL_spliceai		0.94		Position offset: -12

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

Other links and lift over

dbSNP: rs199846428; hg19: chr2-215657181;