chr2-214792454-T-A

Position:

• chr2-214792454-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000465.4(BARD1):​c.216-9A>T variant causes a splice polypyrimidine tract, 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 0.0013 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0037 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BARD1 NM_000465.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002109
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.559

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-214792454-T-A is Benign according to our data. Variant chr2-214792454-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 489669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-214792454-T-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BARD1	NM_000465.4	c.216-9A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000260947.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BARD1	ENST00000260947.9	c.216-9A>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000465.4	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 140 AN: 104426 Hom.: 0 Cov.: 28 FAILED QC

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000691

Gnomad ASJ AF: 0.000782

Gnomad EAS AF: 0.000791

Gnomad SAS AF: 0.000922

Gnomad FIN AF: 0.00309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00365 AC: 4712 AN: 1289906 Hom.: 0 Cov.: 33 AF XY: 0.00459 AC XY: 2910 AN XY: 633326

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0123

Gnomad4 EAS exome AF: 0.00242

Gnomad4 SAS exome AF: 0.0170

Gnomad4 FIN exome AF: 0.0354

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.00250

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00134 AC: 140 AN: 104442 Hom.: 0 Cov.: 28 AF XY: 0.00153 AC XY: 77 AN XY: 50390

Gnomad4 AFR AF: 0.00110

Gnomad4 AMR AF: 0.000790

Gnomad4 ASJ AF: 0.000782

Gnomad4 EAS AF: 0.000794

Gnomad4 SAS AF: 0.000928

Gnomad4 FIN AF: 0.00309

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00153 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Mar 20, 2017	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 16, 2015	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 22, 2015	- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Counsyl

Aug 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.17
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0020
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

Publications

LitVar

Other links and lift over

dbSNP: rs759575504; hg19: chr2-215657178;