chr7-66639180-A-T

Variant names:

• chr7-66639180-A-T
• rs387907261
• NM_153033.5:c.818A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_153033.5(KCTD7):​c.818A>T​(p.Asn273Ile) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCTD7 NM_153033.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.01
• Publications: 5 publications found

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

ENSG00000284461 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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, 7 uncertain in NM_153033.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-66639180-A-T is Pathogenic according to our data. Variant chr7-66639180-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37011.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.30090898). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCTD7	NM_153033.5	c.818A>T	p.Asn273Ile	missense_variant	Exon 4 of 4	ENST00000639828.2	NP_694578.1
KCTD7	NM_001167961.2	c.818A>T	p.Asn273Ile	missense_variant	Exon 4 of 5		NP_001161433.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCTD7	ENST00000639828.2	c.818A>T	p.Asn273Ile	missense_variant	Exon 4 of 4	2	NM_153033.5	ENSP00000492240.1
ENSG00000284461	ENST00000503687.2	n.397+251A>T		intron_variant	Intron 3 of 12	2		ENSP00000421074.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Progressive myoclonic epilepsy type 3 Pathogenic:1

Jun 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	T;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L;.;L;.
PhyloP100		4.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.5	.;.;N;.
REVEL	Benign	0.26
Sift	Benign	0.056	.;.;T;.
Sift4G	Benign	0.11	.;.;T;.
Polyphen		0.84	P;.;.;.
Vest4		0.78
MutPred		0.43		Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);.;
MVP		0.87
ClinPred		0.67	D
GERP RS		4.2
PromoterAI		-0.00010	Neutral
Varity_R		0.25
gMVP		0.57
Mutation Taster		=58/42	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387907261; hg19: chr7-66104167;