1-150627573-C-T

Position:

• chr1-150627573-C-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>A​(p.Gly26Asp) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENSA NM_004436.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ENSA (HGNC:):

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=0.081599206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENSA	NM_004436.4	c.77G>A	p.Gly26Asp	missense_variant	2/4	ENST00000369014.10	NP_004427.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENSA	ENST00000369014.10	c.77G>A	p.Gly26Asp	missense_variant	2/4	1	NM_004436.4	ENSP00000358010.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000810 AC: 2 AN: 247052 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133652

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

Feb 21, 2024

The c.77G>A (p.G26D) alteration is located in exon 2 (coding exon 2) of the ENSA gene. This alteration results from a G to A substitution at nucleotide position 77, causing the glycine (G) at amino acid position 26 to be replaced by an aspartic acid (D). 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	Benign	0.25
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.023	T;T;.;.;.;.;.;.;.;.;.;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.062
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;.;D;D
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.082	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.69	.;N;.;.;N;.;N;.;.;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N;N;N;N;N;.;N;N;N;N;N;N
REVEL	Benign	0.083
Sift	Benign	0.49	T;T;T;T;T;.;T;T;T;D;T;D
Sift4G	Benign	0.13	T;T;T;T;T;.;T;T;T;T;T;T
Polyphen		0.16, 0.13, 0.69, 0.90, 0.74, 1.0	.;B;B;P;P;.;.;P;.;D;.;D
Vest4		0.32
MutPred		0.34		Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);.;Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.67
MPC		1.5
ClinPred		0.15	T
GERP RS		4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.057
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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;