NM_001142730.3:c.1916C>T

Variant names:

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

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>T​(p.Pro639Leu) 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: Orphanet, G2P, 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, 0.796
• PP5: Variant 18-26501144-G-A is Pathogenic according to our data. Variant chr18-26501144-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55883.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD1	NM_001142730.3	MANE Select	c.1916C>T	p.Pro639Leu	missense	Exon 2 of 5	NP_001136202.1	A0A2U3U043
	KCTD1	NM_001258222.3		c.116C>T	p.Pro39Leu	missense	Exon 2 of 5	NP_001245151.1
	KCTD1	NM_001136205.2		c.92C>T	p.Pro31Leu	missense	Exon 2 of 5	NP_001129677.1	Q719H9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCTD1	ENST00000580059.7	TSL:3 MANE Select	c.1916C>T	p.Pro639Leu	missense	Exon 2 of 5	ENSP00000463041.2	A0A2U3U043
	KCTD1	ENST00000408011.7	TSL:1	c.92C>T	p.Pro31Leu	missense	Exon 2 of 5	ENSP00000384367.3	Q719H9
	KCTD1	ENST00000579973.5	TSL:1	c.92C>T	p.Pro31Leu	missense	Exon 3 of 6	ENSP00000464170.1	Q719H9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Scalp-ear-nipple syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.7	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.040	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.40		Loss of disorder (P = 0.0455)
MVP		0.60
MPC		1.6
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.88
gMVP		0.70
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; COSMIC: COSV58690237;