18-26455775-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001142730.3(KCTD1):c.2566G>A(p.Val856Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,614,070 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00098 (3 hom.)
• Consequence: KCTD1 NM_001142730.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.02

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.038848937).
• BP6: Variant 18-26455775-C-T is Benign according to our data. Variant chr18-26455775-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2048230.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 126 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD1	NM_001142730.3	c.2566G>A	p.Val856Ile	missense_variant	5/5	ENST00000580059.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD1	ENST00000580059.7	c.2566G>A	p.Val856Ile	missense_variant	5/5	3	NM_001142730.3	P1

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000541 AC: 136 AN: 251350 Hom.: 0 AF XY: 0.000530 AC XY: 72 AN XY: 135858

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000862

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000977 AC: 1428 AN: 1461826 Hom.: 3 Cov.: 32 AF XY: 0.000927 AC XY: 674 AN XY: 727224

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.000828 AC: 126 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74432

Gnomad4 AFR AF: 0.000723

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000867 Hom.: 0

Bravo AF: 0.000933

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000872

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

The c.2566G>A (p.V856I) alteration is located in exon 5 (coding exon 5) of the KCTD1 gene. This alteration results from a G to A substitution at nucleotide position 2566, causing the valine (V) at amino acid position 856 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.0098	T;T;T;T;.;T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.039	T;T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.34	N;N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.47	T;T;T;T;.;.
Polyphen		0.0070	B;B;B;B;.;.
Vest4		0.24
MVP		0.12
MPC		0.48
ClinPred		0.012	T
GERP RS		6.0
Varity_R		0.15
gMVP		0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs151239539; hg19: chr18-24035739; COSMIC: COSV99049542; COSMIC: COSV99049542;