rs371919994

chr7-66629140-G-Cchr7-66629140-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_153033.5(KCTD7):c.76G>C(p.Asp26His) variant causes a missense change. The variant allele was found at a frequency of 0.000000724 in 1,381,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D26Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.17

Genes affected

KCTD7 (HGNC:21957): (potassium channel tetramerization domain containing 7) This gene encodes a member of the potassium channel tetramerization domain-containing protein family. Family members are identified on a structural basis and contain an amino-terminal domain similar to the T1 domain present in the voltage-gated potassium channel. Mutations in this gene have been associated with progressive myoclonic epilepsy-3. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a chain BTB/POZ domain-containing protein KCTD7 (size 288) in uniprot entity KCTD7_HUMAN there are 29 pathogenic changes around while only 4 benign (88%) in NM_153033.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19646025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCTD7	NM_153033.5	c.76G>C	p.Asp26His	missense_variant	1/4	ENST00000639828.2
KCTD7	NM_001167961.2	c.76G>C	p.Asp26His	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCTD7	ENST00000639828.2	c.76G>C	p.Asp26His	missense_variant	1/4	2	NM_153033.5	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000593 AC: 1 AN: 168536 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 93724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.24e-7 AC: 1 AN: 1381412 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 685298

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: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000840 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.;.;.;.;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.85	T;T;T;T;T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.20	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N;.;.;N;.;.
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.96	D
Polyphen		0.0030	B;.;.;.;.;.
Vest4		0.27, 0.31
MutPred		0.24		Gain of catalytic residue at L28 (P = 0.0862);Gain of catalytic residue at L28 (P = 0.0862);Gain of catalytic residue at L28 (P = 0.0862);Gain of catalytic residue at L28 (P = 0.0862);Gain of catalytic residue at L28 (P = 0.0862);Gain of catalytic residue at L28 (P = 0.0862);
MVP		0.69
ClinPred		0.46	T
GERP RS		4.0
Varity_R		0.23
gMVP		0.33

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: rs371919994; hg19: chr7-66094127;