12-88565733-G-C

Variant names:

• chr12-88565733-G-C
• rs2046971
• NM_000899.5:c.15+14531C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000899.5(KITLG):​c.15+14531C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 152,122 control chromosomes in the GnomAD database, including 36,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.66 (36723 hom., cov: 32)
• Consequence: KITLG NM_000899.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.239
• Publications: 7 publications found

Genes affected

KITLG (HGNC:6343): (KIT ligand) This gene encodes the ligand of the tyrosine-kinase receptor encoded by the KIT locus. This ligand is a pleiotropic factor that acts in utero in germ cell and neural cell development, and hematopoiesis, all believed to reflect a role in cell migration. In adults, it functions pleiotropically, while mostly noted for its continued requirement in hematopoiesis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

KITLG Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 69

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia
• hyperpigmentation with or without hypopigmentation, familial progressive

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial progressive hyper- and hypopigmentation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial progressive hyperpigmentation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Waardenburg syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• Waardenburg syndrome, IIa 2F

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.795 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000899.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KITLG	NM_000899.5	MANE Select	c.15+14531C>G		intron	N/A	NP_000890.1
	KITLG	NM_003994.6		c.15+14531C>G		intron	N/A	NP_003985.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KITLG	ENST00000644744.1	MANE Select	c.15+14531C>G		intron	N/A	ENSP00000495951.1
	KITLG	ENST00000347404.10	TSL:1	c.15+14531C>G		intron	N/A	ENSP00000054216.5
	KITLG	ENST00000357116.4	TSL:4	c.-48+14531C>G		intron	N/A	ENSP00000474021.1

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100155 AN: 152004 Hom.: 36719 Cov.: 32

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.752

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.858

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.803

Gnomad FIN AF: 0.783

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.800

Gnomad OTH AF: 0.700

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.659 AC: 100179 AN: 152122 Hom.: 36723 Cov.: 32 AF XY: 0.664 AC XY: 49356 AN XY: 74362

African (AFR) AF: 0.302 AC: 12519 AN: 41484

American (AMR) AF: 0.782 AC: 11959 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.858 AC: 2976 AN: 3468

East Asian (EAS) AF: 0.722 AC: 3739 AN: 5176

South Asian (SAS) AF: 0.805 AC: 3881 AN: 4820

European-Finnish (FIN) AF: 0.783 AC: 8279 AN: 10572

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.800 AC: 54408 AN: 67994

Other (OTH) AF: 0.701 AC: 1478 AN: 2108

Alfa AF: 0.720 Hom.: 5247

Bravo AF: 0.640

Asia WGS AF: 0.726 AC: 2524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.9
DANN	Benign	0.65
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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: rs2046971; hg19: chr12-88959510;