18-26501138-T-G

Position:

• chr18-26501138-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_001142730.3(KCTD1):​c.1922A>C​(p.His641Pro) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H641Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD1 NM_001142730.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.60

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-26501139-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280853.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897
• PP5: Variant 18-26501138-T-G is Pathogenic according to our data. Variant chr18-26501138-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 55886.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD1	NM_001142730.3	c.1922A>C	p.His641Pro	missense_variant	2/5	ENST00000580059.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD1	ENST00000580059.7	c.1922A>C	p.His641Pro	missense_variant	2/5	3	NM_001142730.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Scalp-ear-nipple syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	Jan 29, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 04, 2013	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D;D;D;D;.;D;D;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;.;D;.;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.090	D
MutationAssessor	Uncertain	2.2	M;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.7	.;.;D;D;.;.;.;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0050	.;.;D;D;.;.;.;.
Sift4G	Benign	0.13	T;T;T;T;.;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;.
Vest4		0.85
MutPred		0.54		Gain of disorder (P = 0.0558);Gain of disorder (P = 0.0558);Gain of disorder (P = 0.0558);Gain of disorder (P = 0.0558);.;.;Gain of disorder (P = 0.0558);Gain of disorder (P = 0.0558);
MVP		0.94
MPC		2.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.96

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: rs587777001; hg19: chr18-24081102;