12-88532513-CAAAA-CAAA

Variant names:

• chr12-88532513-CA-C
• rs11428619
• NM_000899.5:c.130-11delT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000899.5(KITLG):​c.130-11delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,162,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 30)
  • Exomes 𝑓: 0.034 (0 hom.)
• Consequence: KITLG NM_000899.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.318
• Publications: 3 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 -8 ACMG points.

• BP6: Variant 12-88532513-CA-C is Benign according to our data. Variant chr12-88532513-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1272999.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KITLG	NM_000899.5	MANE Select	c.130-11delT		intron	N/A	NP_000890.1
	KITLG	NM_003994.6		c.130-11delT		intron	N/A	NP_003985.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KITLG	ENST00000644744.1	MANE Select	c.130-11delT		intron	N/A	ENSP00000495951.1
	KITLG	ENST00000347404.10	TSL:1	c.130-11delT		intron	N/A	ENSP00000054216.5
	KITLG	ENST00000378535.4	TSL:1	n.73-11delT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000397 AC: 56 AN: 140946 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000711

Gnomad ASJ AF: 0.000603

Gnomad EAS AF: 0.000206

Gnomad SAS AF: 0.000222

Gnomad FIN AF: 0.00129

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000341

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0513 AC: 6095 AN: 118740 AF XY: 0.0500

Gnomad AFR exome AF: 0.0347

Gnomad AMR exome AF: 0.0901

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.0726

Gnomad FIN exome AF: 0.0535

Gnomad NFE exome AF: 0.0380

Gnomad OTH exome AF: 0.0687

GnomAD4 exome AF: 0.0335 AC: 34257 AN: 1021590 Hom.: 0 Cov.: 23 AF XY: 0.0334 AC XY: 16757 AN XY: 502458

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0369 AC: 818 AN: 22190

American (AMR) AF: 0.0589 AC: 1560 AN: 26490

Ashkenazi Jewish (ASJ) AF: 0.0430 AC: 672 AN: 15622

East Asian (EAS) AF: 0.0404 AC: 898 AN: 22208

South Asian (SAS) AF: 0.0448 AC: 2394 AN: 53452

European-Finnish (FIN) AF: 0.0412 AC: 1396 AN: 33860

Middle Eastern (MID) AF: 0.0263 AC: 104 AN: 3958

European-Non Finnish (NFE) AF: 0.0311 AC: 24955 AN: 803350

Other (OTH) AF: 0.0361 AC: 1460 AN: 40460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000397 AC: 56 AN: 140992 Hom.: 0 Cov.: 30 AF XY: 0.000498 AC XY: 34 AN XY: 68318

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000235 AC: 9 AN: 38280

American (AMR) AF: 0.000711 AC: 10 AN: 14070

Ashkenazi Jewish (ASJ) AF: 0.000603 AC: 2 AN: 3318

East Asian (EAS) AF: 0.000207 AC: 1 AN: 4836

South Asian (SAS) AF: 0.000223 AC: 1 AN: 4490

European-Finnish (FIN) AF: 0.00129 AC: 11 AN: 8496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000342 AC: 22 AN: 64420

Other (OTH) AF: 0.00 AC: 0 AN: 1950

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0493 Hom.: 31

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.32
Mutation Taster		=99/1	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: rs11428619; hg19: chr12-88926290; COSMIC: COSV57200966;