rs1057519547

Variant names:

• chr5-45396550-C-A
• rs1057519547
• NM_021072.4:c.1172G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-45396550-C-A
• chr5-45396550-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_021072.4(HCN1):​c.1172G>T​(p.Gly391Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G391S) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91
• Publications: 0 publications found

Genes affected

HCN1 (HGNC:4845): (hyperpolarization activated cyclic nucleotide gated potassium channel 1) The membrane protein encoded by this gene is a hyperpolarization-activated cation channel that contributes to the native pacemaker currents in heart and neurons. The encoded protein can homodimerize or heterodimerize with other pore-forming subunits to form a potassium channel. This channel may act as a receptor for sour tastes. [provided by RefSeq, Oct 2011]

HCN1 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 24

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• generalized epilepsy with febrile seizures plus

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• generalized epilepsy with febrile seizures plus, type 10

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_021072.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-45396551-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 635189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 5-45396550-C-A is Pathogenic according to our data. Variant chr5-45396550-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1074847.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021072.4. 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
	HCN1	NM_021072.4	MANE Select	c.1172G>T	p.Gly391Val	missense	Exon 4 of 8	NP_066550.2	O60741

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCN1	ENST00000303230.6	TSL:1 MANE Select	c.1172G>T	p.Gly391Val	missense	Exon 4 of 8	ENSP00000307342.4	O60741
	HCN1	ENST00000947598.1		c.1169G>T	p.Gly390Val	missense	Exon 4 of 8	ENSP00000617657.1
	HCN1	ENST00000673735.1		c.1172G>T	p.Gly391Val	missense	Exon 4 of 9	ENSP00000501107.1	A0A669KB45

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Developmental and epileptic encephalopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.74	P
Vest4		0.99
MutPred		0.71		Gain of catalytic residue at G391 (P = 0.1918)
MVP		0.99
MPC		3.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.99
Mutation Taster		=7/93	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

Other links and lift over

dbSNP: rs1057519547; hg19: chr5-45396652;