rs878853125

Positions:

• chr18-26501178-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_001142730.3(KCTD1):​c.1882C>T​(p.Pro628Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD1 NM_001142730.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.50

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.824
• PP5: Variant 18-26501178-G-A is Pathogenic according to our data. Variant chr18-26501178-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 235828.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCTD1	NM_001142730.3	c.1882C>T	p.Pro628Ser	missense_variant	2/5	ENST00000580059.7	NP_001136202.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCTD1	ENST00000580059.7	c.1882C>T	p.Pro628Ser	missense_variant	2/5	3	NM_001142730.3	ENSP00000463041	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Scalp-ear-nipple syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Jan 29, 2014

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T;T;T;T;.;T;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.0	L;L;L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.9	.;.;D;D;.;.;.;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0070	D;D;D;D;.;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;.
Vest4		0.86
MutPred		0.29		Gain of glycosylation at P20 (P = 0.0263);Gain of glycosylation at P20 (P = 0.0263);Gain of glycosylation at P20 (P = 0.0263);Gain of glycosylation at P20 (P = 0.0263);.;.;Gain of glycosylation at P20 (P = 0.0263);Gain of glycosylation at P20 (P = 0.0263);
MVP		0.75
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.82
gMVP		0.81

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853125; hg19: chr18-24081142;