dbSNP rs199604642: KCTD7:p.Arg121Ser (chr7-66638299-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_153033.5(KCTD7):c.361C>A(p.Arg121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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. R121L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCTD7
NM_153033.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.49

Publications

0 publications found

Variant links:

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]

KCTD7 Gene-Disease associations (from GenCC):

progressive myoclonic epilepsy type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
progressive myoclonus epilepsy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

KCTD7 links:

ENSG00000284461 (HGNC:):

ENSG00000284461 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_153033.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19584838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5 link	c.361C>A	p.Arg121Ser	missense_variant	Exon 3 of 4	ENST00000639828.2	NP_694578.1	Q96MP8-1A0A024RDN7
KCTD7	NM_001167961.2 link	c.361C>A	p.Arg121Ser	missense_variant	Exon 3 of 5		NP_001161433.1	Q96MP8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2 link	c.361C>A	p.Arg121Ser	missense_variant	Exon 3 of 4	2	NM_153033.5	ENSP00000492240.1		Q96MP8-1
ENSG00000284461	ENST00000503687.2 link	n.191C>A		non_coding_transcript_exon_variant	Exon 2 of 13	2		ENSP00000421074.1		E9PHB8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.;.;.;.;.

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.031

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.20

T;T;T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.055

N;.;.;N;.;.

PhyloP100

3.5

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.030

.;N;.;N;.;.

REVEL

Uncertain

0.32

Sift

Benign

0.40

.;T;.;T;.;.

Sift4G

Benign

0.73

.;T;.;T;.;.

Polyphen

0.029

B;.;.;.;.;.

Vest4

0.65, 0.65

MutPred

0.49

Gain of phosphorylation at R121 (P = 0.0219);Gain of phosphorylation at R121 (P = 0.0219);Gain of phosphorylation at R121 (P = 0.0219);Gain of phosphorylation at R121 (P = 0.0219);Gain of phosphorylation at R121 (P = 0.0219);Gain of phosphorylation at R121 (P = 0.0219);

MVP

0.81

ClinPred

0.48

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.73

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over