11-78174146-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001029859.3(KCTD21):c.409T>A(p.Ser137Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KCTD21 NM_001029859.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

Genes affected

KCTD21 (HGNC:27452): (potassium channel tetramerization domain containing 21) Enables cullin family protein binding activity; histone deacetylase binding activity; and identical protein binding activity. Involved in negative regulation of smoothened signaling pathway and ubiquitin-dependent protein catabolic process. [provided by Alliance of Genome Resources, Apr 2022]

KCTD21-AS1 (HGNC:48674): (KCTD21 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22757715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD21	NM_001029859.3	c.409T>A	p.Ser137Thr	missense_variant	2/2	ENST00000340067.4
KCTD21	XM_047426803.1	c.517T>A	p.Ser173Thr	missense_variant	3/3
KCTD21	XM_006718517.3	c.409T>A	p.Ser137Thr	missense_variant	3/3
KCTD21	XM_006718518.4	c.409T>A	p.Ser137Thr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD21	ENST00000340067.4	c.409T>A	p.Ser137Thr	missense_variant	2/2	1	NM_001029859.3	P1
KCTD21-AS1	ENST00000662186.1	n.1154A>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2022

The c.409T>A (p.S137T) alteration is located in exon 2 (coding exon 1) of the KCTD21 gene. This alteration results from a T to A substitution at nucleotide position 409, causing the serine (S) at amino acid position 137 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.019	T;T;.
Eigen	Benign	-0.017
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.
MutationTaster	Benign	0.91	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.070
Sift	Benign	0.090	T;D;D
Sift4G	Benign	0.34	T;.;.
Polyphen		0.30	B;.;.
Vest4		0.37
MutPred		0.41		Loss of disorder (P = 0.04);Loss of disorder (P = 0.04);Loss of disorder (P = 0.04);
MVP		0.48
MPC		0.57
ClinPred		0.57	D
GERP RS		5.8
Varity_R		0.14
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-77885192;