Genetic Variant HYCC1:p.Pro466Arg (chr7-22945758-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032581.4(HYCC1):c.1397C>G(p.Pro466Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P466L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HYCC1
NM_032581.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

Publications

0 publications found

Variant links:

Genes affected

HYCC1 (HGNC:24587): (hyccin PI4KA lipid kinase complex subunit 1) The protein encoded by this gene may play a part in the beta-catenin/Lef signaling pathway. Expression of this gene is down-regulated by beta-catenin. Defects in this gene are a cause of hypomyelination with congenital cataract (HCC). [provided by RefSeq, Oct 2008]

HYCC1 Gene-Disease associations (from GenCC):

hypomyelinating leukodystrophy 5
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P

HYCC1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10702932).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HYCC1	NM_032581.4 link	c.1397C>G	p.Pro466Arg	missense_variant	Exon 11 of 11	ENST00000432176.7	NP_115970.2	Q9BYI3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYCC1	ENST00000432176.7 link	c.1397C>G	p.Pro466Arg	missense_variant	Exon 11 of 11	1	NM_032581.4	ENSP00000403396.2		Q9BYI3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33458

American (AMR)

AF:

0.0000224

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111838

Other (OTH)

AF:

0.00

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.077

Eigen

Benign

-0.17

Eigen_PC

Benign

0.044

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.57

M_CAP

Benign

0.0070

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.20

PhyloP100

3.4

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.4

REVEL

Benign

0.20

Sift

Benign

0.17

Sift4G

Benign

0.63

Polyphen

0.0020

Vest4

0.35

MutPred

0.28

Loss of glycosylation at P466 (P = 0.0534);

MVP

0.32

MPC

0.14

ClinPred

0.46

GERP RS

5.3

Varity_R

0.039

gMVP

0.23

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over