Genetic Variant ENSG00000284461:n.-46C>A (chr7-66629019-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000503687.2(ENSG00000284461):n.-46C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000755 in 1,325,010 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.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

ENSG00000284461
ENST00000503687.2 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0240

Publications

0 publications found

Variant links:

Genes affected

ENSG00000284461 (HGNC:):

ENSG00000284461 links:

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5 link	c.-46C>A		5_prime_UTR_variant	Exon 1 of 4	ENST00000639828.2	NP_694578.1	Q96MP8-1A0A024RDN7
KCTD7	NM_001167961.2 link	c.-46C>A		5_prime_UTR_variant	Exon 1 of 5		NP_001161433.1	Q96MP8-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENSG00000284461	ENST00000503687.2 link	n.-46C>A	non_coding_transcript_exon_variant	Exon 1 of 13	2		ENSP00000421074.1	E9PHB8
KCTD7	ENST00000639828.2 link	c.-46C>A	5_prime_UTR_variant	Exon 1 of 4	2	NM_153033.5	ENSP00000492240.1	Q96MP8-1
ENSG00000284461	ENST00000503687.2 link	n.-46C>A	5_prime_UTR_variant	Exon 1 of 13	2		ENSP00000421074.1	E9PHB8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.55e-7

AC:

AN:

1325010

Hom.:

Cov.:

AF XY:

0.00000153

AC XY:

AN XY:

653580

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26702

American (AMR)

AF:

0.00

AC:

AN:

27704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22726

East Asian (EAS)

AF:

0.00

AC:

AN:

27828

South Asian (SAS)

AF:

0.0000136

AC:

AN:

73300

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45170

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4564

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1042956

Other (OTH)

AF:

0.00

AC:

AN:

54060

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

9.1

(source)

DANN

Benign

0.70

PhyloP100

0.024

PromoterAI

0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over