18-26479292-A-G

Variant names:

• chr18-26479292-A-G
• rs6508445
• NM_001142730.3:c.1989-2633T>C

Variant summary

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

The NM_001142730.3(KCTD1):​c.1989-2633T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.737 in 151,956 control chromosomes in the GnomAD database, including 41,961 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 0.74 (41961 hom., cov: 30)
• Consequence: KCTD1 NM_001142730.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 2 publications found

Genes affected

KCTD1 (HGNC:18249): (potassium channel tetramerization domain containing 1) This gene encodes a protein containing a BTB (Broad-complex, tramtrack and bric a brac), also known as a POZ (POxvirus and zinc finger) protein-protein interaction domain. The encoded protein negatively regulates the AP-2 family of transcription factors and the Wnt signaling pathway. A mechanism for the modulation of Wnt signaling has been proposed in which the encoded protein enhances ubiquitination and degradation of the beta-catenin protein. Mutations in this gene have been identified in Scalp-ear-nipple (SEN) syndrome. [provided by RefSeq, May 2017]

KCTD1 Gene-Disease associations (from GenCC):

• scalp-ear-nipple syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142730.3. 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
	KCTD1	NM_001142730.3	MANE Select	c.1989-2633T>C		intron	N/A	NP_001136202.1
	KCTD1	NM_001258222.3		c.189-2633T>C		intron	N/A	NP_001245151.1
	KCTD1	NM_001136205.2		c.165-2633T>C		intron	N/A	NP_001129677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD1	ENST00000580059.7	TSL:3 MANE Select	c.1989-2633T>C		intron	N/A	ENSP00000463041.2
	KCTD1	ENST00000408011.7	TSL:1	c.165-2633T>C		intron	N/A	ENSP00000384367.3
	KCTD1	ENST00000579973.5	TSL:1	c.165-2633T>C		intron	N/A	ENSP00000464170.1

Frequencies

GnomAD3 genomes AF: 0.737 AC: 111873 AN: 151838 Hom.: 41956 Cov.: 30

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.860

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.834

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.855

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.765

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

GnomAD4 genome AF: 0.737 AC: 111916 AN: 151956 Hom.: 41961 Cov.: 30 AF XY: 0.733 AC XY: 54465 AN XY: 74254

African (AFR) AF: 0.608 AC: 25222 AN: 41462

American (AMR) AF: 0.755 AC: 11543 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.834 AC: 2894 AN: 3472

East Asian (EAS) AF: 0.994 AC: 5093 AN: 5126

South Asian (SAS) AF: 0.854 AC: 4098 AN: 4796

European-Finnish (FIN) AF: 0.642 AC: 6779 AN: 10556

Middle Eastern (MID) AF: 0.837 AC: 246 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53641 AN: 67948

Other (OTH) AF: 0.767 AC: 1617 AN: 2108

Alfa AF: 0.785 Hom.: 93140

Bravo AF: 0.740

Asia WGS AF: 0.895 AC: 3113 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.67
DANN	Benign	0.78
PhyloP100		-1.0
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: rs6508445; hg19: chr18-24059256;