KCNH1 p.Lys217Asn

Variant names:

• chr1-211019164-C-A
• NM_172362.3:c.651G>T
• KCNH1 p.Lys217Asn

Your query was ambiguous. Multiple possible variants found:

• chr1-211019164-C-A
• chr1-211019164-C-G

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM2 PP3_Moderate

The NM_172362.3(KCNH1):​c.651G>T​(p.Lys217Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNH1 NM_172362.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.16
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• KCNH1 associated disorder

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Illumina
• Temple-Baraitser syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Zimmermann-Laband syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• Zimmermann-Laband syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_172362.3 (KCNH1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172362.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH1	NM_172362.3	MANE Select	c.651G>T	p.Lys217Asn	missense	Exon 6 of 11	NP_758872.1	O95259-1
	KCNH1	NM_002238.4		c.651G>T	p.Lys217Asn	missense	Exon 6 of 11	NP_002229.1	O95259-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNH1	ENST00000271751.10	TSL:2 MANE Select	c.651G>T	p.Lys217Asn	missense	Exon 6 of 11	ENSP00000271751.4	O95259-1
	KCNH1	ENST00000639952.1	TSL:1	c.651G>T	p.Lys217Asn	missense	Exon 6 of 11	ENSP00000492697.1	O95259-2
	KCNH1	ENST00000640044.1	TSL:1	c.310+84332G>T		intron	N/A	ENSP00000491434.1	A0A1W2PPA2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
PromoterAI		-0.031	Neutral
Varity_R		0.96
gMVP		0.96
Mutation Taster		=3/97	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-211192506;