6-55248710-G-T

Position:

• chr6-55248710-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001384272.1(HCRTR2):​c.295G>T​(p.Ala99Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HCRTR2 NM_001384272.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

Genes affected

HCRTR2 (HGNC:4849): (hypocretin receptor 2) The protein encoded by this gene is a G-protein coupled receptor involved in the regulation of feeding behavior. The encoded protein binds the hypothalamic neuropeptides orexin A and orexin B. A related gene (HCRTR1) encodes a G-protein coupled receptor that selectively binds orexin A. [provided by RefSeq, Jan 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCRTR2	NM_001384272.1	c.295G>T	p.Ala99Ser	missense_variant	2/7	ENST00000370862.4
HCRTR2	NM_001526.5	c.295G>T	p.Ala99Ser	missense_variant	3/8
HCRTR2	XM_017010798.2	c.295G>T	p.Ala99Ser	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCRTR2	ENST00000370862.4	c.295G>T	p.Ala99Ser	missense_variant	2/7	1	NM_001384272.1	P1
HCRTR2	ENST00000615358.4	c.295G>T	p.Ala99Ser	missense_variant	3/8	1		P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.295G>T (p.A99S) alteration is located in exon 2 (coding exon 2) of the HCRTR2 gene. This alteration results from a G to T substitution at nucleotide position 295, causing the alanine (A) at amino acid position 99 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.4	.;N
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.33	T;T
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.80		Loss of stability (P = 0.0378);Loss of stability (P = 0.0378);
MVP		0.94
MPC		1.1
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.63
gMVP		0.74

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: chr6-55113508;