11-2161163-C-CGCAA

Variant names:

• chr11-2161163-C-CGCAA
• rs3842740
• ENST00000250971.7:c.-40_-39insTTGC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000207.3(INS):​c.-18+4_-18+5insTTGC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0205 in 737,138 control chromosomes in the GnomAD database, including 1,550 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.068 (1118 hom., cov: 34)
  • Exomes 𝑓: 0.0083 (432 hom.)
• Consequence: INS NM_000207.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.23
• Publications: 7 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 -9 ACMG points.

• BP6: Variant 11-2161163-C-CGCAA is Benign according to our data. Variant chr11-2161163-C-CGCAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 304060.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	NM_000207.3	MANE Select	c.-18+4_-18+5insTTGC		splice_region intron	N/A	NP_000198.1
	INS	NM_001185097.2		c.-40_-39insTTGC		5_prime_UTR	Exon 1 of 3	NP_001172026.1
	INS	NM_001185098.2		c.-193_-192insTTGC		5_prime_UTR	Exon 1 of 2	NP_001172027.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INS	ENST00000250971.7	TSL:1	c.-40_-39insTTGC		5_prime_UTR	Exon 1 of 3	ENSP00000250971.3
	INS	ENST00000397262.5	TSL:1	c.-193_-192insTTGC		5_prime_UTR	Exon 1 of 2	ENSP00000380432.1
	INS	ENST00000381330.5	TSL:1 MANE Select	c.-18+4_-18+5insTTGC		splice_region intron	N/A	ENSP00000370731.5

Frequencies

GnomAD3 genomes AF: 0.0675 AC: 10275 AN: 152134 Hom.: 1112 Cov.: 34

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.0507

GnomAD4 exome AF: 0.00828 AC: 4844 AN: 584886 Hom.: 432 Cov.: 7 AF XY: 0.00727 AC XY: 2185 AN XY: 300438

African (AFR) AF: 0.229 AC: 3318 AN: 14496

American (AMR) AF: 0.0198 AC: 382 AN: 19296

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 67 AN: 14526

East Asian (EAS) AF: 0.00 AC: 0 AN: 31570

South Asian (SAS) AF: 0.000679 AC: 33 AN: 48606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29248

Middle Eastern (MID) AF: 0.0145 AC: 33 AN: 2276

European-Non Finnish (NFE) AF: 0.00110 AC: 432 AN: 394432

Other (OTH) AF: 0.0190 AC: 579 AN: 30436

GnomAD4 genome AF: 0.0676 AC: 10297 AN: 152252 Hom.: 1118 Cov.: 34 AF XY: 0.0657 AC XY: 4891 AN XY: 74454

African (AFR) AF: 0.231 AC: 9569 AN: 41502

American (AMR) AF: 0.0329 AC: 503 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 68006

Other (OTH) AF: 0.0501 AC: 106 AN: 2114

Alfa AF: 0.0588 Hom.: 87

Bravo AF: 0.0787

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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	not provided (1)
-	-	1	Transient Neonatal Diabetes, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3842740; hg19: chr11-2182393;