chr18-26476639-C-T

Variant names:

• chr18-26476639-C-T
• rs587777003
• NM_001142730.3:c.2009G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001142730.3(KCTD1):​c.2009G>A​(p.Gly670Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCTD1 NM_001142730.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.81
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 18-26476639-C-T is Pathogenic according to our data. Variant chr18-26476639-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55888.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2009G>A	p.Gly670Asp	missense	Exon 3 of 5	NP_001136202.1
	KCTD1	NM_001258222.3		c.209G>A	p.Gly70Asp	missense	Exon 3 of 5	NP_001245151.1
	KCTD1	NM_001136205.2		c.185G>A	p.Gly62Asp	missense	Exon 3 of 5	NP_001129677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD1	ENST00000580059.7	TSL:3 MANE Select	c.2009G>A	p.Gly670Asp	missense	Exon 3 of 5	ENSP00000463041.2
	KCTD1	ENST00000408011.7	TSL:1	c.185G>A	p.Gly62Asp	missense	Exon 3 of 5	ENSP00000384367.3
	KCTD1	ENST00000579973.5	TSL:1	c.185G>A	p.Gly62Asp	missense	Exon 4 of 6	ENSP00000464170.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Scalp-ear-nipple syndrome Pathogenic:3

Jan 29, 2014

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Apr 04, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

May 06, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as a heterozygous change in patients with Scalp-ear-nipple syndrome (PMID: 10517259, 23541344). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.185G>A (p.Gly62Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.185G>A (p.Gly62Asp) variant is classified as Likely Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.52		Gain of helix (P = 0.132)
MVP		0.55
MPC		1.8
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.86
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs587777003; hg19: chr18-24056603;