11-626946-G-A

Variant names:

• chr11-626946-G-A
• rs890866680
• NM_021920.4:c.115C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021920.4(SCT):​c.115C>T​(p.Arg39Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00003 in 1,534,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: SCT NM_021920.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

Genes affected

SCT (HGNC:10607): (secretin) This gene encodes a member of the glucagon family of peptides. The encoded preproprotein is secreted by endocrine S cells in the proximal small intestinal mucosa as a prohormone, then proteolytically processed to generate the mature peptide hormone. The release of this active peptide hormone is stimulated by either fatty acids or acidic pH in the duodenum. This hormone stimulates the secretion of bile and bicarbonate in the duodenum, pancreatic and biliary ducts. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34655005).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCT	NM_021920.4	c.115C>T	p.Arg39Cys	missense_variant	Exon 2 of 4	ENST00000176195.4	NP_068739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCT	ENST00000176195.4	c.115C>T	p.Arg39Cys	missense_variant	Exon 2 of 4	1	NM_021920.4	ENSP00000176195.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151990 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000154 AC: 2 AN: 130186 AF XY: 0.0000281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000821

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000311 AC: 43 AN: 1382804 Hom.: 0 Cov.: 33 AF XY: 0.0000308 AC XY: 21 AN XY: 682384

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 31454

Gnomad4 AMR exome AF: 0.0000561 AC: 2 AN: 35622

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25108

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35670

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 79096

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 35588

Gnomad4 NFE exome AF: 0.0000352 AC: 38 AN: 1078026

Gnomad4 Remaining exome AF: 0.0000520 AC: 3 AN: 57690

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151990 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74248

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.0000655 AC: 0.0000654622 AN: 0.0000654622

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.000029436 AN: 0.000029436

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.115C>T (p.R39C) alteration is located in exon 2 (coding exon 2) of the SCT gene. This alteration results from a C to T substitution at nucleotide position 115, causing the arginine (R) at amino acid position 39 to be replaced by a cysteine (C). 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	Pathogenic	0.80
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.52	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.21	B
Vest4		0.37
MutPred		0.59		Loss of MoRF binding (P = 0.0038);
MVP		0.38
MPC		0.98
ClinPred		0.65	D
GERP RS		0.50
Varity_R		0.56
gMVP		0.15
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs890866680; hg19: chr11-626946;