1-222527017-C-G

Variant names:

• chr1-222527017-C-G
• NM_024746.4:c.1757G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024746.4(HHIPL2):​c.1757G>C​(p.Ser586Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HHIPL2 NM_024746.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

Genes affected

HHIPL2 (HGNC:25842): (HHIP like 2) Predicted to enable catalytic activity. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HHIPL2	NM_024746.4	c.1757G>C	p.Ser586Thr	missense_variant	Exon 7 of 9	ENST00000343410.7	NP_079022.2
HHIPL2	XM_024449814.2	c.1757G>C	p.Ser586Thr	missense_variant	Exon 7 of 10		XP_024305582.1
HHIPL2	XM_011509986.2	c.1757G>C	p.Ser586Thr	missense_variant	Exon 7 of 8		XP_011508288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HHIPL2	ENST00000343410.7	c.1757G>C	p.Ser586Thr	missense_variant	Exon 7 of 9	1	NM_024746.4	ENSP00000342118.6
HHIPL2	ENST00000468172.1	n.376G>C		non_coding_transcript_exon_variant	Exon 3 of 5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1757G>C (p.S586T) alteration is located in exon 7 (coding exon 7) of the HHIPL2 gene. This alteration results from a G to C substitution at nucleotide position 1757, causing the serine (S) at amino acid position 586 to be replaced by a threonine (T). 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	Benign	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Pathogenic	3.2	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.18
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.36		Gain of glycosylation at S586 (P = 0.0415);
MVP		0.29
MPC		0.55
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.47
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -48

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: chr1-222700359;