rs755382547

Variant names:

• chr5-51384649-C-G
• rs755382547
• NM_002202.3:c.137C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-51384649-C-G
• chr5-51384649-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002202.3(ISL1):​c.137C>G​(p.Ala46Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ISL1 NM_002202.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15
• Publications: 3 publications found

Genes affected

ISL1 (HGNC:6132): (ISL LIM homeobox 1) This gene encodes a member of the LIM/homeodomain family of transcription factors. The encoded protein binds to the enhancer region of the insulin gene, among others, and may play an important role in regulating insulin gene expression. The encoded protein is central to the development of pancreatic cell lineages and may also be required for motor neuron generation. Mutations in this gene have been associated with maturity-onset diabetes of the young. [provided by RefSeq, Jul 2008]

ISL1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002202.3. 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
	ISL1	NM_002202.3	MANE Select	c.137C>G	p.Ala46Gly	missense	Exon 2 of 6	NP_002193.2	P61371

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISL1	ENST00000230658.12	TSL:1 MANE Select	c.137C>G	p.Ala46Gly	missense	Exon 2 of 6	ENSP00000230658.7	P61371
	ISL1	ENST00000511384.1	TSL:5	c.137C>G	p.Ala46Gly	missense	Exon 2 of 6	ENSP00000422676.1	D6RBJ1
	ISL1	ENST00000967706.1		c.28+950C>G		intron	N/A	ENSP00000637765.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Bladder exstrophy-epispadias-cloacal extrophy complex (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Benign	1.5	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.54
MutPred		0.59		Loss of stability (P = 0.0967)
MVP		0.73
MPC		1.2
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.33
gMVP		0.50
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs755382547; hg19: chr5-50680483;