rs3842752

Variant names:

• chr11-2159843-G-A
• rs3842752
• NM_000207.3:c.*9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000207.3(INS):​c.*9C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,609,784 control chromosomes in the GnomAD database, including 34,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2322 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31767 hom.)
• Consequence: INS NM_000207.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -5.12
• Publications: 57 publications found

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]

ENSG00000295384 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004797995).
• BP6: Variant 11-2159843-G-A is Benign according to our data. Variant chr11-2159843-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000207.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.*9C>T		3_prime_UTR	Exon 3 of 3	NP_000198.1
	INS	NM_001185097.2		c.*9C>T		3_prime_UTR	Exon 3 of 3	NP_001172026.1
	INS	NM_001185098.2		c.*9C>T		3_prime_UTR	Exon 2 of 2	NP_001172027.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000381330.5	TSL:1 MANE Select	c.*9C>T		3_prime_UTR	Exon 3 of 3	ENSP00000370731.5
	INS	ENST00000250971.7	TSL:1	c.*9C>T		3_prime_UTR	Exon 3 of 3	ENSP00000250971.3
	INS	ENST00000397262.5	TSL:1	c.*9C>T		3_prime_UTR	Exon 2 of 2	ENSP00000380432.1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25164 AN: 152042 Hom.: 2320 Cov.: 33

Gnomad AFR AF: 0.0982

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.0414

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.173 AC: 42022 AN: 243204 AF XY: 0.173

Gnomad AFR exome AF: 0.0953

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.217

Gnomad EAS exome AF: 0.0371

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.204 AC: 296864 AN: 1457624 Hom.: 31767 Cov.: 37 AF XY: 0.202 AC XY: 146109 AN XY: 724800

African (AFR) AF: 0.0924 AC: 3091 AN: 33458

American (AMR) AF: 0.171 AC: 7583 AN: 44314

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 5577 AN: 26032

East Asian (EAS) AF: 0.0351 AC: 1392 AN: 39622

South Asian (SAS) AF: 0.130 AC: 11094 AN: 85538

European-Finnish (FIN) AF: 0.154 AC: 8020 AN: 52050

Middle Eastern (MID) AF: 0.108 AC: 623 AN: 5756

European-Non Finnish (NFE) AF: 0.223 AC: 248227 AN: 1110640

Other (OTH) AF: 0.187 AC: 11257 AN: 60214

GnomAD4 genome AF: 0.165 AC: 25162 AN: 152160 Hom.: 2322 Cov.: 33 AF XY: 0.160 AC XY: 11905 AN XY: 74396

African (AFR) AF: 0.0979 AC: 4066 AN: 41528

American (AMR) AF: 0.161 AC: 2462 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 743 AN: 3468

East Asian (EAS) AF: 0.0413 AC: 214 AN: 5176

South Asian (SAS) AF: 0.130 AC: 626 AN: 4826

European-Finnish (FIN) AF: 0.155 AC: 1644 AN: 10604

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14803 AN: 67958

Other (OTH) AF: 0.140 AC: 296 AN: 2108

Alfa AF: 0.196 Hom.: 8066

Bravo AF: 0.162

TwinsUK AF: 0.221 AC: 820

ALSPAC AF: 0.238 AC: 918

ESP6500AA AF: 0.0942 AC: 413

ESP6500EA AF: 0.221 AC: 1897

ExAC AF: 0.172 AC: 20732

Asia WGS AF: 0.0930 AC: 324 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal recessive DOPA responsive dystonia (1)
-	-	1	Maturity onset diabetes mellitus in young (1)
-	-	1	Maturity-onset diabetes of the young type 10 (1)
-	-	1	Transient Neonatal Diabetes, Dominant/Recessive (1)
-	-	-	Hypoinsulinemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	0.51
DANN	Benign	0.94
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
PhyloP100		-5.1
PROVEAN	Benign	2.3	N
REVEL	Benign	0.23
Sift	Benign	0.046	D
ClinPred		0.0080	T
GERP RS		-0.36
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3842752; hg19: chr11-2181073; COSMIC: COSV51746935; COSMIC: COSV51746935;