2-214792458-TAAAA-TA

Position:

• chr2-214792458-TAAAA-TA

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP6_Very_Strong BS1 BS2_Supporting

The NM_000465.4(BARD1):​c.216-16_216-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,396,112 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: BARD1 NM_000465.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.804

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 -13 ACMG points.

• BP6: Variant 2-214792458-TAAA-T is Benign according to our data. Variant chr2-214792458-TAAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 490957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00191 (2428/1268842) while in subpopulation AMR AF= 0.00678 (163/24058). AF 95% confidence interval is 0.00593. There are 1 homozygotes in gnomad4_exome. There are 1219 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BARD1	NM_000465.4	c.216-16_216-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.216-16_216-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000465.4	ENSP00000260947	P2

Frequencies

GnomAD3 genomes AF: 0.0000707 AC: 9 AN: 127240 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000230

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000305

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000338

Gnomad OTH AF: 0.000574

GnomAD3 exomes AF: 0.00582 AC: 561 AN: 96390 Hom.: 1 AF XY: 0.00612 AC XY: 322 AN XY: 52578

Gnomad AFR exome AF: 0.00509

Gnomad AMR exome AF: 0.00895

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.000601

Gnomad SAS exome AF: 0.00606

Gnomad FIN exome AF: 0.00628

Gnomad NFE exome AF: 0.00594

Gnomad OTH exome AF: 0.00551

GnomAD4 exome AF: 0.00191 AC: 2428 AN: 1268842 Hom.: 1 AF XY: 0.00194 AC XY: 1219 AN XY: 628372

Gnomad4 AFR exome AF: 0.00198

Gnomad4 AMR exome AF: 0.00678

Gnomad4 ASJ exome AF: 0.00231

Gnomad4 EAS exome AF: 0.000300

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.00240

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.0000707 AC: 9 AN: 127270 Hom.: 0 Cov.: 0 AF XY: 0.0000491 AC XY: 3 AN XY: 61158

Gnomad4 AFR AF: 0.0000290

Gnomad4 AMR AF: 0.000230

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000305

Gnomad4 NFE AF: 0.0000339

Gnomad4 OTH AF: 0.000570

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 24, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56130510; hg19: chr2-215657182;