2-200981496-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001321623.1(HYCC2):c.1535C>T(p.Ser512Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HYCC2 NM_001321623.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.60

Genes affected

HYCC2 (HGNC:28593): (hyccin PI4KA lipid kinase complex subunit 2) Predicted to be involved in phosphatidylinositol phosphate biosynthetic process and protein localization to plasma membrane. Predicted to be located in cytosol. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HYCC2	NM_001321623.1	c.1535C>T	p.Ser512Leu	missense_variant	13/13	ENST00000681958.1
LOC105373835	XR_007088050.1	n.199+17866G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HYCC2	ENST00000681958.1	c.1535C>T	p.Ser512Leu	missense_variant	13/13		NM_001321623.1	P3
HYCC2	ENST00000418596.7	c.1367C>T	p.Ser456Leu	missense_variant	12/12	1		A1
HYCC2	ENST00000286181.7	c.*1288C>T		3_prime_UTR_variant, NMD_transcript_variant	14/14	1
	ENST00000413848.1	n.368+17866G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

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 06, 2022

The c.1367C>T (p.S456L) alteration is located in exon 12 (coding exon 10) of the FAM126B gene. This alteration results from a C to T substitution at nucleotide position 1367, causing the serine (S) at amino acid position 456 to be replaced by a leucine (L). 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	0.25
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.2	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.71
MutPred		0.40		Loss of disorder (P = 0.0212);
MVP		0.85
MPC		1.0
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.60
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs2042022272; hg19: chr2-201846219;