chr18-26501144-G-C

Variant names:

• chr18-26501144-G-C
• rs587776999
• NM_001142730.3:c.1916C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_001142730.3(KCTD1):​c.1916C>G​(p.Pro639Arg) 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. P639H) 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: 9.50
• Publications: 6 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-26501144-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 55884.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817
• PP5: Variant 18-26501144-G-C is Pathogenic according to our data. Variant chr18-26501144-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 55882.Status of the report is no_assertion_criteria_provided, 0 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.1916C>G	p.Pro639Arg	missense	Exon 2 of 5	NP_001136202.1
	KCTD1	NM_001258222.3		c.116C>G	p.Pro39Arg	missense	Exon 2 of 5	NP_001245151.1
	KCTD1	NM_001136205.2		c.92C>G	p.Pro31Arg	missense	Exon 2 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.1916C>G	p.Pro639Arg	missense	Exon 2 of 5	ENSP00000463041.2
	KCTD1	ENST00000408011.7	TSL:1	c.92C>G	p.Pro31Arg	missense	Exon 2 of 5	ENSP00000384367.3
	KCTD1	ENST00000579973.5	TSL:1	c.92C>G	p.Pro31Arg	missense	Exon 3 of 6	ENSP00000464170.1

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

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.0	L
PhyloP100		9.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.48		Gain of catalytic residue at P31 (P = 0.0044)
MVP		0.58
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.76
Mutation Taster		=0/100	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: rs587776999; hg19: chr18-24081108;