2-214809599-C-G

Variant names:

• chr2-214809599-C-G
• rs1129804
• ENST00000613192.2:n.-30G>C

Variant summary

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

The ENST00000613192.2(BARD1):​n.-30G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,529,042 control chromosomes in the GnomAD database, including 391,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41389 hom., cov: 35)
  • Exomes 𝑓: 0.71 (350315 hom.)
• Consequence: BARD1 ENST00000613192.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.234
• Publications: 28 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=-0.85).
• BP6: Variant 2-214809599-C-G is Benign according to our data. Variant chr2-214809599-C-G is described in ClinVar as Benign. ClinVar VariationId is 334199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BARD1	NM_000465.4	c.-30G>C		5_prime_UTR_variant	Exon 1 of 11	ENST00000260947.9	NP_000456.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BARD1	ENST00000260947.9	c.-30G>C		5_prime_UTR_variant	Exon 1 of 11	1	NM_000465.4	ENSP00000260947.4

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111994 AN: 152010 Hom.: 41325 Cov.: 35

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.762

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.711

Gnomad OTH AF: 0.721

GnomAD2 exomes AF: 0.734 AC: 102538 AN: 139724 AF XY: 0.726

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.815

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.804

Gnomad FIN exome AF: 0.782

Gnomad NFE exome AF: 0.708

Gnomad OTH exome AF: 0.713

GnomAD4 exome AF: 0.712 AC: 980672 AN: 1376914 Hom.: 350315 Cov.: 50 AF XY: 0.710 AC XY: 481575 AN XY: 677870

African (AFR) AF: 0.761 AC: 23901 AN: 31422

American (AMR) AF: 0.810 AC: 28957 AN: 35740

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 17847 AN: 25104

East Asian (EAS) AF: 0.767 AC: 27245 AN: 35512

South Asian (SAS) AF: 0.668 AC: 52999 AN: 79396

European-Finnish (FIN) AF: 0.782 AC: 27517 AN: 35168

Middle Eastern (MID) AF: 0.687 AC: 3077 AN: 4480

European-Non Finnish (NFE) AF: 0.707 AC: 758001 AN: 1072780

Other (OTH) AF: 0.718 AC: 41128 AN: 57312

GnomAD4 genome AF: 0.737 AC: 112116 AN: 152128 Hom.: 41389 Cov.: 35 AF XY: 0.739 AC XY: 54998 AN XY: 74380

African (AFR) AF: 0.759 AC: 31511 AN: 41506

American (AMR) AF: 0.784 AC: 11992 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2504 AN: 3470

East Asian (EAS) AF: 0.801 AC: 4129 AN: 5158

South Asian (SAS) AF: 0.668 AC: 3220 AN: 4820

European-Finnish (FIN) AF: 0.762 AC: 8083 AN: 10602

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

European-Non Finnish (NFE) AF: 0.711 AC: 48311 AN: 67960

Other (OTH) AF: 0.724 AC: 1533 AN: 2116

Alfa AF: 0.722 Hom.: 7277

Bravo AF: 0.741

Asia WGS AF: 0.740 AC: 2572 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Familial cancer of breast Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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	-0.85
CADD	Benign	6.0
DANN	Benign	0.40
PhyloP100		-0.23
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs1129804; hg19: chr2-215674323;