rs689

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is . The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000207.3(INS):c.-17-6T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,609,954 control chromosomes in the GnomAD database, including 415,985 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 32035 hom., cov: 35)

Exomes 𝑓: 0.72 ( 383950 hom. )

Consequence

INS
NM_000207.3 splice_region, intron

Scores

Splicing: ADA: 0.1228

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0740

Publications

239 publications found

Variant links:

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 links:

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]

INS-IGF2 links:

ENSG00000295384 (HGNC:):

ENSG00000295384 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000207.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 11-2160994-A-T is Benign according to our data. Variant chr11-2160994-A-T is described in ClinVar as Benign. ClinVar VariationId is 304059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.926 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
INS	NM_000207.3	MANE Select	c.-17-6T>A	splice_region intron	N/A	NP_000198.1	P01308-1
INS	NM_001185098.2		c.-23T>A	5_prime_UTR	Exon 1 of 2	NP_001172027.1	P01308-1
INS-IGF2	NM_001042376.3		c.-17-6T>A	splice_region intron	N/A	NP_001035835.1	F8WCM5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
INS	ENST00000397262.5	TSL:1	c.-23T>A	5_prime_UTR	Exon 1 of 2	ENSP00000380432.1	P01308-1
INS	ENST00000381330.5	TSL:1 MANE Select	c.-17-6T>A	splice_region intron	N/A	ENSP00000370731.5	P01308-1
INS-IGF2	ENST00000397270.1	TSL:1	c.-17-6T>A	splice_region intron	N/A	ENSP00000380440.1	F8WCM5-1

Frequencies

GnomAD3 genomes

AF:

0.611

AC:

92830

AN:

152032

Hom.:

32028

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.666

Gnomad AMR

AF:

0.725

Gnomad ASJ

AF:

0.709

Gnomad EAS

AF:

0.947

Gnomad SAS

AF:

0.831

Gnomad FIN

AF:

0.792

Gnomad MID

AF:

0.788

Gnomad NFE

AF:

0.719

Gnomad OTH

AF:

0.669

GnomAD2 exomes

AF:

0.734

AC:

178240

AN:

242726

AF XY:

0.745

show subpopulations

Gnomad AFR exome

AF:

0.247

Gnomad AMR exome

AF:

0.769

Gnomad ASJ exome

AF:

0.703

Gnomad EAS exome

AF:

0.953

Gnomad FIN exome

AF:

0.797

Gnomad NFE exome

AF:

0.720

Gnomad OTH exome

AF:

0.737

GnomAD4 exome

AF:

0.720

AC:

1049977

AN:

1457804

Hom.:

383950

Cov.:

AF XY:

0.725

AC XY:

525501

AN XY:

725156

show subpopulations

African (AFR)

AF:

0.245

AC:

8177

AN:

33438

American (AMR)

AF:

0.762

AC:

33884

AN:

44470

Ashkenazi Jewish (ASJ)

AF:

0.705

AC:

18395

AN:

26076

East Asian (EAS)

AF:

0.959

AC:

38023

AN:

39664

South Asian (SAS)

AF:

0.827

AC:

71293

AN:

86168

European-Finnish (FIN)

AF:

0.792

AC:

40663

AN:

51324

Middle Eastern (MID)

AF:

0.789

AC:

4293

AN:

5442

European-Non Finnish (NFE)

AF:

0.713

AC:

792116

AN:

1110992

Other (OTH)

AF:

0.716

AC:

43133

AN:

60230

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

17870

35741

53611

71482

89352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19814

39628

59442

79256

99070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.610

AC:

92854

AN:

152150

Hom.:

32035

Cov.:

AF XY:

0.624

AC XY:

46388

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.263

AC:

10901

AN:

41518

American (AMR)

AF:

0.725

AC:

11094

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.709

AC:

2461

AN:

3470

East Asian (EAS)

AF:

0.948

AC:

4894

AN:

5164

South Asian (SAS)

AF:

0.831

AC:

4010

AN:

4824

European-Finnish (FIN)

AF:

0.792

AC:

8397

AN:

10602

Middle Eastern (MID)

AF:

0.793

AC:

233

AN:

294

European-Non Finnish (NFE)

AF:

0.719

AC:

48839

AN:

67968

Other (OTH)

AF:

0.673

AC:

1422

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1574

3149

4723

6298

7872

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

750

1500

2250

3000

3750

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.676

Hom.:

6698

Bravo

AF:

0.588

Asia WGS

AF:

0.841

AC:

2925

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Maturity-onset diabetes of the young type 10 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

5.2

(source)

DANN

Benign

0.75

PhyloP100

-0.074

PromoterAI

0.018

Neutral

(source)

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.12

dbscSNV1_RF

Benign

0.39

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.38

Position offset: -6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over