2-214792457-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_000465.4(BARD1):​c.216-12A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BARD1 NM_000465.4 intron
• Scores: Splicing: ADA: 0.00004557
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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):

• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-214792457-T-A is Benign according to our data. Variant chr2-214792457-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 801889.Status of the report is criteria_provided_single_submitter, 1 stars.

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.216-12A>T		intron	N/A	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.159-12A>T		intron	N/A	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.215+4604A>T		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.216-12A>T		intron	N/A	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.159-12A>T		intron	N/A	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.216-12A>T		intron	N/A	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 15 AN: 114574 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000989

Gnomad AMI AF: 0.00134

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000568

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000131

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000869 AC: 8 AN: 92048 AF XY: 0.000119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000542

Gnomad NFE exome AF: 0.0000734

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000388 AC: 52 AN: 1338870 Hom.: 0 Cov.: 33 AF XY: 0.0000317 AC XY: 21 AN XY: 662054

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

African (AFR) AF: 0.000145 AC: 4 AN: 27640

American (AMR) AF: 0.0000744 AC: 2 AN: 26876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23050

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

South Asian (SAS) AF: 0.0000289 AC: 2 AN: 69284

European-Finnish (FIN) AF: 0.000756 AC: 30 AN: 39708

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

European-Non Finnish (NFE) AF: 0.0000123 AC: 13 AN: 1059650

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 Data not reliable, filtered out with message: AS_VQSR AF: 0.000131 AC: 15 AN: 114574 Hom.: 0 Cov.: 29 AF XY: 0.0000905 AC XY: 5 AN XY: 55256

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

African (AFR) AF: 0.0000989 AC: 3 AN: 30348

American (AMR) AF: 0.00 AC: 0 AN: 10602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2758

East Asian (EAS) AF: 0.00 AC: 0 AN: 4394

South Asian (SAS) AF: 0.00 AC: 0 AN: 3502

European-Finnish (FIN) AF: 0.000568 AC: 4 AN: 7048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000131 AC: 7 AN: 53422

Other (OTH) AF: 0.00 AC: 0 AN: 1518

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.026
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199846428; hg19: chr2-215657181;