2-214809521-C-T

Variant names:

• chr2-214809521-C-T
• rs746495820
• NM_000465.4:c.49G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM1 BS2

The NM_000465.4(BARD1):​c.49G>A​(p.Gly17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000764 in 1,439,994 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 2.77
• Publications: 5 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 53 uncertain in NM_000465.4
• BS2: High AC in GnomAdExome4 at 11 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.49G>A	p.Gly17Arg	missense	Exon 1 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.49G>A	p.Gly17Arg	missense	Exon 1 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.49G>A	p.Gly17Arg	missense	Exon 1 of 7	NP_001269474.1	C9IYG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	ENST00000260947.9	TSL:1 MANE Select	c.49G>A	p.Gly17Arg	missense	Exon 1 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.49G>A	p.Gly17Arg	missense	Exon 1 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.49G>A	p.Gly17Arg	missense	Exon 1 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000959 AC: 2 AN: 208470 AF XY: 0.00000865

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: 0.0000218

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000764 AC: 11 AN: 1439994 Hom.: 0 Cov.: 74 AF XY: 0.00000699 AC XY: 5 AN XY: 715106

African (AFR) AF: 0.00 AC: 0 AN: 32974

American (AMR) AF: 0.0000231 AC: 1 AN: 43234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25742

East Asian (EAS) AF: 0.00 AC: 0 AN: 38630

South Asian (SAS) AF: 0.00 AC: 0 AN: 84400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000816 AC: 9 AN: 1103328

Other (OTH) AF: 0.0000168 AC: 1 AN: 59564

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000169 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Familial cancer of breast (3)
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.95	P
Vest4		0.24
MutPred		0.15		Gain of MoRF binding (P = 0.0162)
MVP		0.99
MPC		0.47
ClinPred		0.97	D
GERP RS		4.0
PromoterAI		-0.0071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.47
Mutation Taster		=80/20	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: rs746495820; hg19: chr2-215674245;