chr2-214809702-A-C

Variant names:

• chr2-214809702-A-C
• rs2106172848
• ENST00000797167.1:n.176+57A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000797167.1(SNHG31):​n.176+57A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000472 in 1,060,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 37)
  • Exomes 𝑓: 0.0000047 (0 hom.)
• Consequence: SNHG31 ENST00000797167.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.352
• Publications: 0 publications found

Genes affected

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

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):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.-133T>G		upstream_gene_variant		ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.-133T>G		upstream_gene_variant		1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes Cov.: 37

GnomAD4 exome AF: 0.00000472 AC: 5 AN: 1060058 Hom.: 0 Cov.: 15 AF XY: 0.00000190 AC XY: 1 AN XY: 525392

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

African (AFR) AF: 0.00 AC: 0 AN: 24394

American (AMR) AF: 0.00 AC: 0 AN: 29782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20262

East Asian (EAS) AF: 0.00 AC: 0 AN: 33006

South Asian (SAS) AF: 0.00 AC: 0 AN: 66614

European-Finnish (FIN) AF: 0.0000324 AC: 1 AN: 30898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3298

European-Non Finnish (NFE) AF: 0.00000372 AC: 3 AN: 805786

Other (OTH) AF: 0.0000217 AC: 1 AN: 46018

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000534442), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 37

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.1
DANN	Benign	0.35
PhyloP100		-0.35
PromoterAI		0.099	Neutral
Mutation Taster		=300/0	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: rs2106172848; hg19: chr2-215674426;