rs5507

chr11-2160013-G-Achr11-2160013-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000207.3(INS):c.188-16C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,571,286 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (10 hom.)
• Consequence: INS NM_000207.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.12

Genes affected

INS (HGNC:6081): (insulin) This gene encodes insulin, a peptide hormone that plays a vital role in the regulation of carbohydrate and lipid metabolism. After removal of the precursor signal peptide, proinsulin is post-translationally cleaved into three peptides: the B chain and A chain peptides, which are covalently linked via two disulfide bonds to form insulin, and C-peptide. Binding of insulin to the insulin receptor (INSR) stimulates glucose uptake. A multitude of mutant alleles with phenotypic effects have been identified, including insulin-dependent diabetes mellitus, permanent neonatal diabetes diabetes mellitus, maturity-onset diabetes of the young type 10 and hyperproinsulinemia. There is a read-through gene, INS-IGF2, which overlaps with this gene at the 5' region and with the IGF2 gene at the 3' region. [provided by RefSeq, May 2020]

INS-IGF2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 11-2160013-G-A is Benign according to our data. Variant chr11-2160013-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00587 (894/152298) while in subpopulation AFR AF= 0.0197 (819/41574). AF 95% confidence interval is 0.0186. There are 12 homozygotes in gnomad4. There are 426 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 894 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.188-16C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000381330.5
INS-IGF2	NR_003512.4	n.246+772C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000381330.5	c.188-16C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000207.3	P1

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 894 AN: 152180 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00130 AC: 238 AN: 183460 Hom.: 1 AF XY: 0.000993 AC XY: 98 AN XY: 98664

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.000660

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000140

Gnomad SAS exome AF: 0.0000800

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.000406

GnomAD4 exome AF: 0.000662 AC: 939 AN: 1418988 Hom.: 10 Cov.: 35 AF XY: 0.000596 AC XY: 419 AN XY: 702736

Gnomad4 AFR exome AF: 0.0210

Gnomad4 AMR exome AF: 0.00140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.0000491

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00587 AC: 894 AN: 152298 Hom.: 12 Cov.: 33 AF XY: 0.00572 AC XY: 426 AN XY: 74480

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.00697

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 10, 2018	- -

Neonatal diabetes mellitus Benign:1

Benign, criteria provided, single submitter

clinical testing;curation

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 18, 2011

- -

Neonatal insulin-dependent diabetes mellitus Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as this mutation can cause beta cell destruction. However no sufficient evidence is found to ascertain the role of this particular variant rs5507, yet. -

Hyperproinsulinemia;C1852092:Type 1 diabetes mellitus 2;C3150617:Maturity-onset diabetes of the young type 10;C5394307:Diabetes mellitus, permanent neonatal 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
Cadd	Benign	0.77
Dann	Benign	0.65

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

LitVar

Other links and lift over

dbSNP: rs5507; hg19: chr11-2181243;