11-78174302-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001029859.3(KCTD21):c.253G>T(p.Asp85Tyr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCTD21 NM_001029859.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.11

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD21	NM_001029859.3	c.253G>T	p.Asp85Tyr	missense_variant	2/2	ENST00000340067.4
KCTD21	XM_047426803.1	c.361G>T	p.Asp121Tyr	missense_variant	3/3
KCTD21	XM_006718517.3	c.253G>T	p.Asp85Tyr	missense_variant	3/3
KCTD21	XM_006718518.4	c.253G>T	p.Asp85Tyr	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD21	ENST00000340067.4	c.253G>T	p.Asp85Tyr	missense_variant	2/2	1	NM_001029859.3	P1
KCTD21-AS1	ENST00000662186.1	n.1310C>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Jan 08, 2024

The c.253G>T (p.D85Y) alteration is located in exon 2 (coding exon 1) of the KCTD21 gene. This alteration results from a G to T substitution at nucleotide position 253, causing the aspartic acid (D) at amino acid position 85 to be replaced by a tyrosine (Y). 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	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D;.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-7.3	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;.;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.87
MutPred		0.51		Loss of phosphorylation at Y87 (P = 0.0606);Loss of phosphorylation at Y87 (P = 0.0606);Loss of phosphorylation at Y87 (P = 0.0606);Loss of phosphorylation at Y87 (P = 0.0606);
MVP		0.98
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.85
gMVP		0.84

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: chr11-77885348;