3-10338239-C-G

Variant names:

• chr3-10338239-C-G
• rs35678
• NM_001001331.4:c.3357G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001001331.4(ATP2B2):​c.3357G>C​(p.Ala1119Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A1119A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATP2B2 NM_001001331.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.53
• Publications: 25 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)
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104951054).
• BP7: Synonymous conserved (PhyloP=-3.53 with no splicing effect.

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.3357G>C	p.Ala1119Ala	synonymous	Exon 22 of 23	NP_001001331.1	Q01814-1
	ATP2B2	NM_001438646.1		c.3264G>C	p.Ala1088Ala	synonymous	Exon 20 of 21	NP_001425575.1
	ATP2B2	NM_001353564.1		c.3222G>C	p.Ala1074Ala	synonymous	Exon 20 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.3357G>C	p.Ala1119Ala	synonymous	Exon 22 of 23	ENSP00000353414.2	Q01814-1
	ATP2B2	ENST00000452124.2	TSL:1	c.3264G>C	p.Ala1088Ala	synonymous	Exon 19 of 20	ENSP00000414854.2	Q01814-8
	ATP2B2	ENST00000397077.6	TSL:1	c.3222G>C	p.Ala1074Ala	synonymous	Exon 19 of 20	ENSP00000380267.1	Q01814-6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.013
DANN	Benign	0.79
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.10	T
PhyloP100		-3.5
GERP RS		-9.2
Mutation Taster		=100/0	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: rs35678; hg19: chr3-10379923;