13-113650408-G-C

Position:

• chr13-113650408-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000705.4(ATP4B):​c.712C>G​(p.Gln238Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATP4B NM_000705.4 missense, splice_region
• Scores: Splicing: ADA: 0.1941
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

Genes affected

ATP4B (HGNC:820): (ATPase H+/K+ transporting subunit beta) The protein encoded by this gene belongs to a family of P-type cation-transporting ATPases. The gastric H+, K+-ATPase is a heterodimer consisting of a high molecular weight catalytic alpha subunit and a smaller but heavily glycosylated beta subunit. This enzyme is a proton pump that catalyzes the hydrolysis of ATP coupled with the exchange of H(+) and K(+) ions across the plasma membrane. It is also responsible for gastric acid secretion. This gene encodes the beta subunit of the gastric H+, K+-ATPase. [provided by RefSeq, Jul 2008]

GRK1 (HGNC:10013): (G protein-coupled receptor kinase 1) This gene encodes a member of the guanine nucleotide-binding protein (G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates rhodopsin and initiates its deactivation. Defects in GRK1 are known to cause Oguchi disease 2 (also known as stationary night blindness Oguchi type-2). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP4B	NM_000705.4	c.712C>G	p.Gln238Glu	missense_variant, splice_region_variant	6/7	ENST00000335288.5	NP_000696.1
GRK1	XM_047430493.1	c.-7+2164G>C		intron_variant			XP_047286449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP4B	ENST00000335288.5	c.712C>G	p.Gln238Glu	missense_variant, splice_region_variant	6/7	1	NM_000705.4	ENSP00000334216.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2024

The c.712C>G (p.Q238E) alteration is located in exon 6 (coding exon 6) of the ATP4B gene. This alteration results from a C to G substitution at nucleotide position 712, causing the glutamine (Q) at amino acid position 238 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.25
Sift	Uncertain	0.027	D
Sift4G	Benign	0.10	T
Polyphen		0.94	P
Vest4		0.67
MutPred		0.82		Gain of ubiquitination at K235 (P = 0.037);
MVP		0.61
MPC		0.38
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.17
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.34
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-114304723;