rs2286492

Positions:

• chr7-22945391-A-C
• chr7-22945391-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032581.4(HYCC1):​c.*198T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0908 in 592,352 control chromosomes in the GnomAD database, including 2,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (533 hom., cov: 32)
  • Exomes 𝑓: 0.096 (2115 hom.)
• Consequence: HYCC1 NM_032581.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0580

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-22945391-A-C is Benign according to our data. Variant chr7-22945391-A-C is described in ClinVar as [Benign]. Clinvar id is 359764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-22945391-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HYCC1	NM_032581.4	c.*198T>G		3_prime_UTR_variant	11/11	ENST00000432176.7	NP_115970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HYCC1	ENST00000432176	c.*198T>G		3_prime_UTR_variant	11/11	1	NM_032581.4	ENSP00000403396.2

Frequencies

GnomAD3 genomes AF: 0.0754 AC: 11470 AN: 152064 Hom.: 533 Cov.: 32

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0677

Gnomad ASJ AF: 0.0980

Gnomad EAS AF: 0.115

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0793

GnomAD4 exome AF: 0.0962 AC: 42341 AN: 440170 Hom.: 2115 Cov.: 3 AF XY: 0.0971 AC XY: 22563 AN XY: 232300

Gnomad4 AFR exome AF: 0.0136

Gnomad4 AMR exome AF: 0.0571

Gnomad4 ASJ exome AF: 0.104

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.0967

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.0994

Gnomad4 OTH exome AF: 0.0878

GnomAD4 genome AF: 0.0753 AC: 11464 AN: 152182 Hom.: 533 Cov.: 32 AF XY: 0.0766 AC XY: 5700 AN XY: 74404

Gnomad4 AFR AF: 0.0170

Gnomad4 AMR AF: 0.0676

Gnomad4 ASJ AF: 0.0980

Gnomad4 EAS AF: 0.115

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.0781

Alfa AF: 0.0972 Hom.: 1087

Bravo AF: 0.0676

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

Hypomyelination and Congenital Cataract Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.68

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: rs2286492; hg19: chr7-22985010;