chr2-214809617-A-G

Variant names:

• chr2-214809617-A-G
• rs17489363
• NM_000465.4:c.-48T>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.-48T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,522,770 control chromosomes in the GnomAD database, including 390,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (41405 hom., cov: 36)
  • Exomes 𝑓: 0.71 (349154 hom.)
• Consequence: BARD1 NM_000465.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.58
• Publications: 35 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=-0.89).
• BP6: Variant 2-214809617-A-G is Benign according to our data. Variant chr2-214809617-A-G is described in ClinVar as Benign. ClinVar VariationId is 334200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

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.-48T>C		5_prime_UTR	Exon 1 of 11	NP_000456.2
	BARD1	NM_001282543.2		c.-48T>C		5_prime_UTR	Exon 1 of 10	NP_001269472.1
	BARD1	NM_001282545.2		c.-48T>C		5_prime_UTR	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.-48T>C		5_prime_UTR	Exon 1 of 11	ENSP00000260947.4
	BARD1	ENST00000617164.5	TSL:1	c.-48T>C		5_prime_UTR	Exon 1 of 10	ENSP00000480470.1
	BARD1	ENST00000613706.5	TSL:1	c.-48T>C		5_prime_UTR	Exon 1 of 11	ENSP00000484976.2

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112014 AN: 152012 Hom.: 41341 Cov.: 36

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.783

Gnomad ASJ AF: 0.722

Gnomad EAS AF: 0.804

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: 0.733 AC: 99849 AN: 136150 AF XY: 0.725

Gnomad AFR exome AF: 0.765

Gnomad AMR exome AF: 0.815

Gnomad ASJ exome AF: 0.715

Gnomad EAS exome AF: 0.805

Gnomad FIN exome AF: 0.779

Gnomad NFE exome AF: 0.707

Gnomad OTH exome AF: 0.712

GnomAD4 exome AF: 0.713 AC: 976746 AN: 1370640 Hom.: 349154 Cov.: 39 AF XY: 0.711 AC XY: 478866 AN XY: 673634

African (AFR) AF: 0.761 AC: 23813 AN: 31298

American (AMR) AF: 0.810 AC: 28759 AN: 35498

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 17821 AN: 25052

East Asian (EAS) AF: 0.781 AC: 27581 AN: 35298

South Asian (SAS) AF: 0.667 AC: 52732 AN: 79012

European-Finnish (FIN) AF: 0.782 AC: 26942 AN: 34442

Middle Eastern (MID) AF: 0.688 AC: 2859 AN: 4158

European-Non Finnish (NFE) AF: 0.707 AC: 755311 AN: 1068854

Other (OTH) AF: 0.718 AC: 40928 AN: 57028

GnomAD4 genome AF: 0.737 AC: 112136 AN: 152130 Hom.: 41405 Cov.: 36 AF XY: 0.740 AC XY: 55004 AN XY: 74378

African (AFR) AF: 0.759 AC: 31509 AN: 41502

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

Ashkenazi Jewish (ASJ) AF: 0.722 AC: 2502 AN: 3466

East Asian (EAS) AF: 0.804 AC: 4147 AN: 5160

South Asian (SAS) AF: 0.668 AC: 3219 AN: 4820

European-Finnish (FIN) AF: 0.763 AC: 8081 AN: 10596

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

European-Non Finnish (NFE) AF: 0.711 AC: 48320 AN: 67970

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

Alfa AF: 0.722 Hom.: 7279

Bravo AF: 0.741

Asia WGS AF: 0.740 AC: 2571 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.35
PhyloP100		-2.6
PromoterAI		0.31	Neutral
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: rs17489363; hg19: chr2-215674341;