11-2161163-C-CGCAA

Position:

• chr11-2161163-C-CGCAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_000207.3(INS):​c.-18+4_-18+5insTTGC variant causes a splice donor 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_donor_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.23

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 -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 id is 304060.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.227 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INS	NM_000207.3	c.-18+4_-18+5insTTGC		splice_donor_region_variant, intron_variant		ENST00000381330.5
INS-IGF2	NR_003512.4	n.42+4_42+5insTTGC		splice_donor_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INS	ENST00000250971.7	c.-40_-39insTTGC		5_prime_UTR_variant	1/3	1		P1
INS	ENST00000397262.5	c.-193_-192insTTGC		5_prime_UTR_variant	1/2	1		P1
INS	ENST00000381330.5	c.-18+4_-18+5insTTGC		splice_donor_region_variant, intron_variant		1	NM_000207.3	P1
INS	ENST00000421783.1			upstream_gene_variant		2

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

Gnomad4 AFR exome AF: 0.229

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.00461

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000679

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00110

Gnomad4 OTH exome AF: 0.0190

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

Gnomad4 AFR AF: 0.231

Gnomad4 AMR AF: 0.0329

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00128

Gnomad4 OTH AF: 0.0501

Alfa AF: 0.0588 Hom.: 87

Bravo AF: 0.0787

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

Potent mutations in INS gene can cause early onset diabetes mellitus which is insulin dependent. May have poor response to sulfonylureas, as mutations in this gene can cause beta cell destruction. However no sufficient evidence is found to ascertain the role of this particular variant rs3842740, yet. -

Transient Neonatal Diabetes, Dominant/Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2018

This variant is associated with the following publications: (PMID: 16380501, 20628762, 19247282) -

Autosomal recessive DOPA responsive dystonia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3842740; hg19: chr11-2182393;