18-26455792-G-A

Variant names:

• chr18-26455792-G-A
• rs112720565
• NM_001142730.3:c.2549C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001142730.3(KCTD1):​c.2549C>T​(p.Thr850Met) variant causes a missense change. The variant allele was found at a frequency of 0.00007 in 1,613,960 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000074 (1 hom.)
• Consequence: KCTD1 NM_001142730.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.67
• Publications: 2 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18162751).
• BS2: High AC in GnomAd4 at 5 AD gene.

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.2549C>T	p.Thr850Met	missense	Exon 5 of 5	NP_001136202.1	A0A2U3U043
	KCTD1	NM_001258222.3		c.749C>T	p.Thr250Met	missense	Exon 5 of 5	NP_001245151.1
	KCTD1	NM_001136205.2		c.725C>T	p.Thr242Met	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.2549C>T	p.Thr850Met	missense	Exon 5 of 5	ENSP00000463041.2	A0A2U3U043
	KCTD1	ENST00000408011.7	TSL:1	c.725C>T	p.Thr242Met	missense	Exon 5 of 5	ENSP00000384367.3	Q719H9
	KCTD1	ENST00000579973.5	TSL:1	c.725C>T	p.Thr242Met	missense	Exon 6 of 6	ENSP00000464170.1	Q719H9

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251460 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000739 AC: 108 AN: 1461862 Hom.: 1 Cov.: 32 AF XY: 0.0000770 AC XY: 56 AN XY: 727238

African (AFR) AF: 0.000508 AC: 17 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111992

Other (OTH) AF: 0.000447 AC: 27 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74288

African (AFR) AF: 0.0000724 AC: 3 AN: 41410

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000516 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.051
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	-0.34	N
PhyloP100		5.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.26
Sift	Benign	0.098	T
Sift4G	Benign	0.16	T
Polyphen		0.034	B
Vest4		0.33
MutPred		0.24		Loss of phosphorylation at T242 (P = 0.006)
MVP		0.12
MPC		0.62
ClinPred		0.060	T
GERP RS		6.0
Varity_R		0.10
gMVP		0.47
Mutation Taster		=76/24	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: rs112720565; hg19: chr18-24035756;