5-45261954-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM2 PP2 BP4_Strong BP6_Moderate

The NM_021072.4(HCN1):c.2640C>A(p.Asp880Glu) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HCN1 NM_021072.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.45

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, HCN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.031125098).
• BP6: Variant 5-45261954-G-T is Benign according to our data. Variant chr5-45261954-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2103870.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCN1	NM_021072.4	c.2640C>A	p.Asp880Glu	missense_variant	8/8	ENST00000303230.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCN1	ENST00000303230.6	c.2640C>A	p.Asp880Glu	missense_variant	8/8	1	NM_021072.4	P2
HCN1	ENST00000673735.1	c.*865C>A		3_prime_UTR_variant	9/9			A2
HCN1	ENST00000637305.1	n.1803C>A		non_coding_transcript_exon_variant	7/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.083
Dann	Benign	0.67
DEOGEN2	Benign	0.092	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	-0.42	N
MutationTaster	Benign	0.77	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.034
MutPred		0.094		Gain of helix (P = 0.0425);
MVP		0.56
MPC		0.36
ClinPred		0.035	T
GERP RS		-8.6
Varity_R		0.041
gMVP		0.092

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.

Other links and lift over

hg19: chr5-45262056;