Genetic Variant SCTR:p.Leu312Ile (chr2-119448768-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002980.3(SCTR):c.934C>A(p.Leu312Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000697 in 1,434,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. L312F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SCTR
NM_002980.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.97

Publications

4 publications found

Variant links:

Genes affected

SCTR (HGNC:10608): (secretin receptor) The protein encoded by this gene is a G protein-coupled receptor and belongs to the glucagon-VIP-secretin receptor family. It binds secretin which is the most potent regulator of pancreatic bicarbonate, electrolyte and volume secretion. Secretin and its receptor are suggested to be involved in pancreatic cancer and autism. [provided by RefSeq, Jul 2008]

SCTR links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23979044).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002980.3. 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
	SCTR	NM_002980.3	MANE Select	c.934C>A	p.Leu312Ile	missense	Exon 10 of 13	NP_002971.2	P47872

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCTR	ENST00000019103.8	TSL:1 MANE Select	c.934C>A	p.Leu312Ile	missense	Exon 10 of 13	ENSP00000019103.6	P47872
SCTR	ENST00000903274.1		c.1129C>A	p.Leu377Ile	missense	Exon 12 of 15	ENSP00000573333.1
SCTR	ENST00000903275.1		c.949C>A	p.Leu317Ile	missense	Exon 10 of 13	ENSP00000573334.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

250308

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

6.97e-7

AC:

AN:

1434344

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715506

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32924

American (AMR)

AF:

0.00

AC:

AN:

44660

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25952

East Asian (EAS)

AF:

0.00

AC:

AN:

39574

South Asian (SAS)

AF:

0.00

AC:

AN:

85652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1087130

Other (OTH)

AF:

0.00

AC:

AN:

59416

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.84

M_CAP

Benign

0.0037

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.82

PhyloP100

4.0

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.7

REVEL

Benign

0.063

Sift

Uncertain

0.0040

Sift4G

Benign

0.17

Polyphen

0.052

Vest4

0.28

MutPred

0.67

Gain of catalytic residue at L317 (P = 0.0945)

MVP

0.50

MPC

0.19

ClinPred

0.47

GERP RS

3.4

Varity_R

0.35

gMVP

0.24

Mutation Taster

=73/27

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over