11-2161302-G-C

Variant names:

• chr11-2161302-G-C
• rs748749585

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The variant allele was found at a frequency of 0.0000287 in 313,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: Unknown
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 B:1 O:1
• Conservation: PhyloP100: -2.01

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2161302-G-C is Pathogenic according to our data. Variant chr11-2161302-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 431443.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152022 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000372 AC: 6 AN: 161264 Hom.: 0 Cov.: 0 AF XY: 0.0000245 AC XY: 2 AN XY: 81586

Gnomad4 AFR exome AF: 0.000160

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000764

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000342

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000991

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Benign:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2023	Variant often referred to as c.-331 C>G using alternate nomenclature; Published functional studies demonstrate a damaging effect on promoter activity (Garin et al., 2010; Bonnefond et al., 2011); A different variant at this position (c.-152 C>A) has been reported as likely pathogenic at GeneDx in association with neonatal diabetes; Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 29305569, 24622368, 32252216, 21592955, 20133622, 29183106, 31441606, 32656923, 34101350, 35140529, 33852861, 34458657) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2024	This variant occurs in a non-coding region of the INS gene. It does not change the encoded amino acid sequence of the INS protein. This variant is present in population databases (rs748749585, gnomAD 0.1%). This variant has been observed in individuals with neonatal diabetes (PMID: 20133622). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-331 C>G. ClinVar contains an entry for this variant (Variation ID: 431443). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects INS function (PMID: 21592955). For these reasons, this variant has been classified as Pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 20, 2019

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2024

- -

Diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PS3,PS4,PM2 -

Diabetes mellitus, permanent neonatal 4 Benign:1

Likely benign, flagged submission

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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.rs748749585 variant is Prevalent in patients with Neonatal diabetes mellitus. However, the role of this particular variant is yet to be ascertained -

Permanent neonatal diabetes mellitus Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.59
DANN	Benign	0.74

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs748749585; hg19: chr11-2182532;