rs2286492

Variant names:

• chr7-22945391-A-C
• rs2286492
• NM_032581.4:c.*198T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 14 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 359764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
HYCC1	NM_032581.4	c.*198T>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000432176.7	NP_115970.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HYCC1	ENST00000432176.7	c.*198T>G		3_prime_UTR_variant	Exon 11 of 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

African (AFR) AF: 0.0136 AC: 164 AN: 12090

American (AMR) AF: 0.0571 AC: 1054 AN: 18444

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 1409 AN: 13530

East Asian (EAS) AF: 0.116 AC: 3567 AN: 30770

South Asian (SAS) AF: 0.0967 AC: 4142 AN: 42840

European-Finnish (FIN) AF: 0.109 AC: 3161 AN: 28940

Middle Eastern (MID) AF: 0.0832 AC: 161 AN: 1934

European-Non Finnish (NFE) AF: 0.0994 AC: 26435 AN: 266026

Other (OTH) AF: 0.0878 AC: 2248 AN: 25596

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

African (AFR) AF: 0.0170 AC: 707 AN: 41546

American (AMR) AF: 0.0676 AC: 1031 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.0980 AC: 340 AN: 3468

East Asian (EAS) AF: 0.115 AC: 593 AN: 5162

South Asian (SAS) AF: 0.101 AC: 488 AN: 4828

European-Finnish (FIN) AF: 0.111 AC: 1183 AN: 10628

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6894 AN: 67972

Other (OTH) AF: 0.0781 AC: 165 AN: 2114

Alfa AF: 0.0915 Hom.: 1629

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

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypomyelination and Congenital Cataract Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-0.058
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2286492; hg19: chr7-22985010;