chr1-150627573-C-A

Variant names:

• chr1-150627573-C-A
• rs1482222296
• NM_004436.4:c.77G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004436.4(ENSA):​c.77G>T​(p.Gly26Val) variant causes a missense 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G26D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENSA NM_004436.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82

Genes affected

ENSA (HGNC:3360): (endosulfine alpha) The protein encoded by this gene belongs to a highly conserved cAMP-regulated phosphoprotein (ARPP) family. This protein was identified as an endogenous ligand for the sulfonylurea receptor, ABCC8/SUR1. ABCC8 is the regulatory subunit of the ATP-sensitive potassium (KATP) channel, which is located on the plasma membrane of pancreatic beta cells and plays a key role in the control of insulin release from pancreatic beta cells. This protein is thought to be an endogenous regulator of KATP channels. In vitro studies have demonstrated that this protein modulates insulin secretion through the interaction with KATP channel, and this gene has been proposed as a candidate gene for type 2 diabetes. At least eight alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0819892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENSA	NM_004436.4	c.77G>T	p.Gly26Val	missense_variant	Exon 2 of 4	ENST00000369014.10	NP_004427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSA	ENST00000369014.10	c.77G>T	p.Gly26Val	missense_variant	Exon 2 of 4	1	NM_004436.4	ENSP00000358010.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.85
DEOGEN2	Benign	0.0087	T;T;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.082	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.33	.;N;.;.;N;.;N;.;.;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.88	N;N;N;N;N;.;N;N;N;N;N;N
REVEL	Benign	0.069
Sift	Benign	0.49	T;T;T;T;T;.;T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;.;T;T;T;T;T;T
Polyphen		0.0, 0.010, 0.012, 0.027, 0.0090, 0.98	.;B;B;B;B;.;.;B;.;D;.;D
Vest4		0.18
MutPred		0.46		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;.;Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);
MVP		0.60
MPC		1.0
ClinPred		0.23	T
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.054
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1482222296; hg19: chr1-150600049;