rs5505

Variant names:

• chr11-2160980-G-A
• rs5505
• NM_000207.3:c.-9C>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.-9C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,611,934 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (11 hom., cov: 35)
  • Exomes 𝑓: 0.012 (120 hom.)
• Consequence: INS NM_000207.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.13

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:33527): (INS-IGF2 readthrough) This locus includes two alternatively spliced read-through transcript variants which align to the INS gene in the 5' region and to the IGF2 gene in the 3' region. One transcript is predicted to encode a protein which shares the N-terminus with the INS protein but has a distinct and longer C-terminus, whereas the other transcript is a candidate for nonsense-mediated decay (NMD). The transcripts are imprinted and are paternally expressed in the limb and eye. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-2160980-G-A is Benign according to our data. Variant chr11-2160980-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00872 (1329/152330) while in subpopulation NFE AF= 0.0124 (843/68012). AF 95% confidence interval is 0.0117. There are 11 homozygotes in gnomad4. There are 708 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1329 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INS	NM_000207.3	c.-9C>T		5_prime_UTR_variant	Exon 2 of 3	ENST00000381330.5	NP_000198.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INS	ENST00000381330.5	c.-9C>T		5_prime_UTR_variant	Exon 2 of 3	1	NM_000207.3	ENSP00000370731.5
INS-IGF2	ENST00000397270.1	c.-9C>T		5_prime_UTR_variant	Exon 2 of 5	1		ENSP00000380440.1

Frequencies

GnomAD3 genomes AF: 0.00875 AC: 1332 AN: 152212 Hom.: 11 Cov.: 35

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00562

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00862 AC: 2115 AN: 245352 Hom.: 17 AF XY: 0.00899 AC XY: 1202 AN XY: 133666

Gnomad AFR exome AF: 0.00208

Gnomad AMR exome AF: 0.00436

Gnomad ASJ exome AF: 0.000906

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00657

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0118 AC: 17187 AN: 1459604 Hom.: 120 Cov.: 88 AF XY: 0.0116 AC XY: 8415 AN XY: 726120

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00673

Gnomad4 FIN exome AF: 0.0235

Gnomad4 NFE exome AF: 0.0130

Gnomad4 OTH exome AF: 0.0106

GnomAD4 genome AF: 0.00872 AC: 1329 AN: 152330 Hom.: 11 Cov.: 35 AF XY: 0.00950 AC XY: 708 AN XY: 74492

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.00555

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00517

Gnomad4 FIN AF: 0.0251

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00910 Hom.: 7

Bravo AF: 0.00652

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Apr 16, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

INS: BS1, BS2; INS-IGF2: BS1, BS2 -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neonatal diabetes mellitus Benign:1

Aug 18, 2011

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Diabetes mellitus, permanent neonatal 4 Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

Potent mutations in the INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, mutations in this gene can cause beta cell destruction. However, more evidence is required to confer the association of this particular variant rs5505 with Neonatal diabetes mellitus(PNDM). -

Transient Neonatal Diabetes, Dominant/Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive DOPA responsive dystonia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity-onset diabetes of the young type 10 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.43
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5505; hg19: chr11-2182210;