2-214809557-G-T

Variant names:

• chr2-214809557-G-T
• rs766441081
• NM_000465.4:c.13C>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000465.4(BARD1):​c.13C>A​(p.Arg5Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R5R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BARD1 NM_000465.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.365
• Publications: 4 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 2-214809557-G-T is Benign according to our data. Variant chr2-214809557-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 530250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.365 with no splicing effect.

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.13C>A	p.Arg5Arg	synonymous	Exon 1 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 10	NP_001269472.1
	BARD1	NM_001282545.2		c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 7	NP_001269474.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.13C>A	p.Arg5Arg	synonymous	Exon 1 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 166790 AF XY: 0.00

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: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407832 Hom.: 0 Cov.: 73 AF XY: 0.00 AC XY: 0 AN XY: 696652

African (AFR) AF: 0.00 AC: 0 AN: 32152

American (AMR) AF: 0.00 AC: 0 AN: 39338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 36942

South Asian (SAS) AF: 0.00 AC: 0 AN: 82032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087648

Other (OTH) AF: 0.00 AC: 0 AN: 58436

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Familial cancer of breast (2)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	5.2
DANN	Benign	0.75
PhyloP100		0.36
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Mutation Taster		=100/0	polymorphism

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: rs766441081; hg19: chr2-215674281;