Genetic Variant NM_172362.3:c.1055C>T (chr1-210920047-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP3

The NM_172362.3(KCNH1):c.1055C>T(p.Ser352Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S352Y) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNH1
NM_172362.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.61

Variant links:

Genes affected

KCNH1 (HGNC:6250): (potassium voltage-gated channel subfamily H member 1) Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit of a voltage-gated non-inactivating delayed rectifier potassium channel. It is activated at the onset of myoblast differentiation. The gene is highly expressed in brain and in myoblasts. Overexpression of the gene may confer a growth advantage to cancer cells and favor tumor cell proliferation. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

KCNH1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a transmembrane_region Helical; Voltage-sensor; Name=Segment S4 (size 22) in uniprot entity KCNH1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_172362.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-210920047-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 183419.Status of the report is no_assertion_criteria_provided, 0 stars.

PP2

Missense variant in the KCNH1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 72 curated benign missense variants. Gene score misZ: 3.8156 (above the threshold of 3.09). Trascript score misZ: 5.0674 (above the threshold of 3.09). GenCC associations: The gene is linked to KCNH1 associated disorder, Zimmermann-Laband syndrome, Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNH1	NM_172362.3 link	c.1055C>T	p.Ser352Phe	missense_variant	Exon 7 of 11	ENST00000271751.10	NP_758872.1	O95259-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNH1	ENST00000271751.10 link	c.1055C>T	p.Ser352Phe	missense_variant	Exon 7 of 11	2	NM_172362.3	ENSP00000271751.4		O95259-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726832

show subpopulations

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

.;.;D;.;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;.;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.1

.;.;L;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-4.0

D;.;D;.;.

REVEL

Pathogenic

0.82

Sift

Benign

0.25

T;.;T;.;.

Sift4G

Benign

0.21

T;.;T;.;.

Polyphen

0.97

.;.;D;.;.

Vest4

0.83

MutPred

0.54

.;Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);.;.;

MVP

0.98

MPC

1.8

ClinPred

0.99

GERP RS

5.5

Varity_R

0.61

gMVP

0.95

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over