rs1048108

Variant names:

• chr2-214809500-G-A
• rs1048108
• NM_000465.4:c.70C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-214809500-G-A
• chr2-214809500-G-C
• chr2-214809500-G-T

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.70C>T​(p.Pro24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,603,114 control chromosomes in the GnomAD database, including 107,214 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P24R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.33 (8919 hom., cov: 34)
  • Exomes 𝑓: 0.37 (98295 hom.)
• Consequence: BARD1 NM_000465.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.990
• Publications: 90 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 (MetaRNN=0.0026446283).
• BP6: Variant 2-214809500-G-A is Benign according to our data. Variant chr2-214809500-G-A is described in ClinVar as Benign. ClinVar VariationId is 183698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.394 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BARD1	NM_000465.4	MANE Select	c.70C>T	p.Pro24Ser	missense	Exon 1 of 11	NP_000456.2	Q99728-1
	BARD1	NM_001282543.2		c.70C>T	p.Pro24Ser	missense	Exon 1 of 10	NP_001269472.1	Q99728-2
	BARD1	NM_001282545.2		c.70C>T	p.Pro24Ser	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.70C>T	p.Pro24Ser	missense	Exon 1 of 11	ENSP00000260947.4	Q99728-1
	BARD1	ENST00000617164.5	TSL:1	c.70C>T	p.Pro24Ser	missense	Exon 1 of 10	ENSP00000480470.1	Q99728-2
	BARD1	ENST00000613706.5	TSL:1	c.70C>T	p.Pro24Ser	missense	Exon 1 of 11	ENSP00000484976.2	A0A087X2H0

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50590 AN: 152028 Hom.: 8911 Cov.: 34

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.436

Gnomad EAS AF: 0.361

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.347

Gnomad NFE AF: 0.370

Gnomad OTH AF: 0.343

GnomAD2 exomes AF: 0.384 AC: 87436 AN: 227958 AF XY: 0.383

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.432

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.358

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.377

Gnomad OTH exome AF: 0.363

GnomAD4 exome AF: 0.366 AC: 530737 AN: 1450966 Hom.: 98295 Cov.: 77 AF XY: 0.368 AC XY: 265225 AN XY: 721242

African (AFR) AF: 0.206 AC: 6869 AN: 33328

American (AMR) AF: 0.425 AC: 18758 AN: 44110

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 10825 AN: 25904

East Asian (EAS) AF: 0.349 AC: 13722 AN: 39356

South Asian (SAS) AF: 0.413 AC: 35216 AN: 85336

European-Finnish (FIN) AF: 0.420 AC: 20669 AN: 49178

Middle Eastern (MID) AF: 0.331 AC: 1900 AN: 5746

European-Non Finnish (NFE) AF: 0.362 AC: 401213 AN: 1108060

Other (OTH) AF: 0.360 AC: 21565 AN: 59948

GnomAD4 genome AF: 0.333 AC: 50616 AN: 152148 Hom.: 8919 Cov.: 34 AF XY: 0.336 AC XY: 24997 AN XY: 74372

African (AFR) AF: 0.212 AC: 8810 AN: 41538

American (AMR) AF: 0.386 AC: 5908 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 1512 AN: 3470

East Asian (EAS) AF: 0.361 AC: 1855 AN: 5144

South Asian (SAS) AF: 0.409 AC: 1972 AN: 4826

European-Finnish (FIN) AF: 0.404 AC: 4271 AN: 10582

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.370 AC: 25141 AN: 67974

Other (OTH) AF: 0.342 AC: 724 AN: 2114

Alfa AF: 0.360 Hom.: 5378

Bravo AF: 0.322

TwinsUK AF: 0.362 AC: 1343

ALSPAC AF: 0.360 AC: 1386

ESP6500AA AF: 0.215 AC: 892

ESP6500EA AF: 0.347 AC: 2859

ExAC AF: 0.367 AC: 43728

Asia WGS AF: 0.375 AC: 1304 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Familial cancer of breast (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.99
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.26
Sift	Benign	0.18	T
Sift4G	Benign	0.21	T
Polyphen		0.0020	B
Vest4		0.10
MPC		0.076
ClinPred		0.011	T
GERP RS		3.1
PromoterAI		0.26	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.25
Mutation Taster		=97/3	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: rs1048108; hg19: chr2-215674224; COSMIC: COSV53608734; COSMIC: COSV53608734;