chr5-45261954-G-T

Position:

• chr5-45261954-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 in gene, where missense usually causes diseases (based on misZ statistic), HCN1. . Gene score misZ 3.6647 (greater than the threshold 3.09). Trascript score misZ 3.2427 (greater than threshold 3.09). GenCC has associacion of gene with generalized epilepsy with febrile seizures plus, type 10, undetermined early-onset epileptic encephalopathy, developmental and epileptic encephalopathy, 24, generalized epilepsy with febrile seizures plus.
• 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

Labcorp Genetics (formerly Invitae), Labcorp

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;