18-26455865-C-A

Variant names:

• chr18-26455865-C-A
• rs770919792
• NM_001142730.3:c.2476G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001142730.3(KCTD1):​c.2476G>T​(p.Val826Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V826M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCTD1 NM_001142730.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• 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, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21404329).

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.2476G>T	p.Val826Leu	missense	Exon 5 of 5	NP_001136202.1	A0A2U3U043
	KCTD1	NM_001258222.3		c.676G>T	p.Val226Leu	missense	Exon 5 of 5	NP_001245151.1
	KCTD1	NM_001136205.2		c.652G>T	p.Val218Leu	missense	Exon 5 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.2476G>T	p.Val826Leu	missense	Exon 5 of 5	ENSP00000463041.2	A0A2U3U043
	KCTD1	ENST00000408011.7	TSL:1	c.652G>T	p.Val218Leu	missense	Exon 5 of 5	ENSP00000384367.3	Q719H9
	KCTD1	ENST00000579973.5	TSL:1	c.652G>T	p.Val218Leu	missense	Exon 6 of 6	ENSP00000464170.1	Q719H9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.20	N
PhyloP100		1.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.30
Sift	Benign	0.23	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.27		Gain of loop (P = 0.0502)
MVP		0.42
MPC		0.59
ClinPred		0.61	D
GERP RS		6.0
Varity_R		0.35
gMVP		0.44
Mutation Taster		=68/32	polymorphism

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: rs770919792; hg19: chr18-24035829;