2-214809366-T-G

Variant names:

• chr2-214809366-T-G
• rs35933323
• NM_000465.4:c.158+46A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000465.4(BARD1):​c.158+46A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.717 in 1,606,874 control chromosomes in the GnomAD database, including 414,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41457 hom., cov: 33)
  • Exomes 𝑓: 0.71 (372658 hom.)
• Consequence: BARD1 NM_000465.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.191
• Publications: 14 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]

SNHG31 (HGNC:54196): (small nucleolar RNA host gene 31)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-214809366-T-G is Benign according to our data. Variant chr2-214809366-T-G is described in ClinVar as Benign. ClinVar VariationId is 1174423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.158+46A>C		intron_variant	Intron 1 of 10	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.158+46A>C		intron_variant	Intron 1 of 10	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112103 AN: 152042 Hom.: 41393 Cov.: 33

Gnomad AFR AF: 0.760

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.763

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.721

GnomAD2 exomes AF: 0.739 AC: 172011 AN: 232616 AF XY: 0.730

Gnomad AFR exome AF: 0.766

Gnomad AMR exome AF: 0.820

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.783

Gnomad NFE exome AF: 0.713

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.715 AC: 1039451 AN: 1454714 Hom.: 372658 Cov.: 42 AF XY: 0.712 AC XY: 515331 AN XY: 723318

African (AFR) AF: 0.761 AC: 25356 AN: 33322

American (AMR) AF: 0.815 AC: 36115 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 18441 AN: 25934

East Asian (EAS) AF: 0.792 AC: 31284 AN: 39508

South Asian (SAS) AF: 0.668 AC: 57051 AN: 85442

European-Finnish (FIN) AF: 0.784 AC: 40037 AN: 51086

Middle Eastern (MID) AF: 0.693 AC: 3992 AN: 5758

European-Non Finnish (NFE) AF: 0.707 AC: 783986 AN: 1109240

Other (OTH) AF: 0.718 AC: 43189 AN: 60114

GnomAD4 genome AF: 0.738 AC: 112225 AN: 152160 Hom.: 41457 Cov.: 33 AF XY: 0.740 AC XY: 55050 AN XY: 74386

African (AFR) AF: 0.760 AC: 31535 AN: 41496

American (AMR) AF: 0.784 AC: 11996 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2506 AN: 3472

East Asian (EAS) AF: 0.805 AC: 4163 AN: 5170

South Asian (SAS) AF: 0.669 AC: 3224 AN: 4822

European-Finnish (FIN) AF: 0.763 AC: 8086 AN: 10592

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.711 AC: 48352 AN: 67994

Other (OTH) AF: 0.725 AC: 1528 AN: 2108

Alfa AF: 0.716 Hom.: 9773

Bravo AF: 0.741

Asia WGS AF: 0.741 AC: 2575 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	7.2
DANN	Benign	0.56
PhyloP100		0.19
PromoterAI		0.053	Neutral
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: rs35933323; hg19: chr2-215674090;