18-26501137-G-C

Variant names:

• chr18-26501137-G-C
• NM_001142730.3:c.1923C>G
• KCTD1 p.His641Gln

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1 PM2 PM5 PP3

The NM_001142730.3(KCTD1):​c.1923C>G​(p.His641Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H641P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD1 NM_001142730.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 0 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, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_001142730.3 (KCTD1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-26501138-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 55886.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

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.1923C>G	p.His641Gln	missense	Exon 2 of 5	NP_001136202.1	A0A2U3U043
	KCTD1	NM_001258222.3		c.123C>G	p.His41Gln	missense	Exon 2 of 5	NP_001245151.1
	KCTD1	NM_001136205.2		c.99C>G	p.His33Gln	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.1923C>G	p.His641Gln	missense	Exon 2 of 5	ENSP00000463041.2	A0A2U3U043
	KCTD1	ENST00000408011.7	TSL:1	c.99C>G	p.His33Gln	missense	Exon 2 of 5	ENSP00000384367.3	Q719H9
	KCTD1	ENST00000579973.5	TSL:1	c.99C>G	p.His33Gln	missense	Exon 3 of 6	ENSP00000464170.1	Q719H9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	2.0	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.011	D
Sift4G	Benign	0.11	T
Varity_R		0.93
gMVP		0.71
Mutation Taster		=0/100	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr18-24081101;