rs953627979

Variant names:

• chr3-10328941-G-A
• rs953627979
• NM_001001331.4:c.3605C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-10328941-G-A
• chr3-10328941-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001001331.4(ATP2B2):​c.3605C>T​(p.Pro1202Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,806 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P1202P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000055 (1 hom.)
• Consequence: ATP2B2 NM_001001331.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96
• Publications: 2 publications found

Genes affected

ATP2B2 (HGNC:815): (ATPase plasma membrane Ca2+ transporting 2) The protein encoded by this gene belongs to the family of P-type primary ion transport ATPases characterized by the formation of an aspartyl phosphate intermediate during the reaction cycle. These enzymes remove bivalent calcium ions from eukaryotic cells against very large concentration gradients and play a critical role in intracellular calcium homeostasis. The mammalian plasma membrane calcium ATPase isoforms are encoded by at least four separate genes and the diversity of these enzymes is further increased by alternative splicing of transcripts. The expression of different isoforms and splice variants is regulated in a developmental, tissue- and cell type-specific manner, suggesting that these pumps are functionally adapted to the physiological needs of particular cells and tissues. This gene encodes the plasma membrane calcium ATPase isoform 2. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ATP2B2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal dominant 82

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal recessive nonsyndromic hearing loss 12

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25669092).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001331.4. 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
	ATP2B2	NM_001001331.4	MANE Select	c.3605C>T	p.Pro1202Leu	missense	Exon 23 of 23	NP_001001331.1	Q01814-1
	ATP2B2	NM_001438646.1		c.3512C>T	p.Pro1171Leu	missense	Exon 21 of 21	NP_001425575.1
	ATP2B2	NM_001353564.1		c.3470C>T	p.Pro1157Leu	missense	Exon 21 of 21	NP_001340493.1	Q01814-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP2B2	ENST00000360273.7	TSL:5 MANE Select	c.3605C>T	p.Pro1202Leu	missense	Exon 23 of 23	ENSP00000353414.2	Q01814-1
	ATP2B2	ENST00000452124.2	TSL:1	c.3512C>T	p.Pro1171Leu	missense	Exon 20 of 20	ENSP00000414854.2	Q01814-8
	ATP2B2	ENST00000397077.6	TSL:1	c.3470C>T	p.Pro1157Leu	missense	Exon 20 of 20	ENSP00000380267.1	Q01814-6

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151912 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461894 Hom.: 1 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151912 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74186

African (AFR) AF: 0.0000242 AC: 1 AN: 41320

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.098
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.1	L
PhyloP100		4.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.27
Sift	Benign	0.052	T
Sift4G	Uncertain	0.054	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.16		Loss of glycosylation at P1203 (P = 0.0088)
MVP		0.69
MPC		1.5
ClinPred		0.66	D
GERP RS		5.1
Varity_R		0.066
gMVP		0.68
Mutation Taster		=58/42	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: rs953627979; hg19: chr3-10370625; COSMIC: COSV59503206; COSMIC: COSV59503206;