rs148168726

Variant names:

• chr7-22960315-C-T
• rs148168726
• NM_032581.4:c.932G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_032581.4(HYCC1):​c.932G>A​(p.Arg311Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: HYCC1 NM_032581.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.58
• Publications: 3 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000854 (13/152276) while in subpopulation AFR AF = 0.000241 (10/41554). AF 95% confidence interval is 0.00013. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032581.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYCC1	NM_032581.4	MANE Select	c.932G>A	p.Arg311Gln	missense	Exon 10 of 11	NP_115970.2
	HYCC1	NM_001363466.2		c.932G>A	p.Arg311Gln	missense	Exon 10 of 12	NP_001350395.1	Q9BYI3-3
	HYCC1	NM_001363467.2		c.932G>A	p.Arg311Gln	missense	Exon 10 of 12	NP_001350396.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HYCC1	ENST00000432176.7	TSL:1 MANE Select	c.932G>A	p.Arg311Gln	missense	Exon 10 of 11	ENSP00000403396.2	Q9BYI3-1
	HYCC1	ENST00000440481.6	TSL:1	c.500G>A	p.Arg167Gln	missense	Exon 9 of 11	ENSP00000397168.2	H7C0W7
	HYCC1	ENST00000905181.1		c.932G>A	p.Arg311Gln	missense	Exon 10 of 11	ENSP00000575240.1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251360 AF XY: 0.0000515

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461442 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 727052

African (AFR) AF: 0.000120 AC: 4 AN: 33458

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111742

Other (OTH) AF: 0.0000828 AC: 5 AN: 60366

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74470

African (AFR) AF: 0.000241 AC: 10 AN: 41554

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hypomyelination and Congenital Cataract (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.055	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.023	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.27
MPC		0.52
ClinPred		0.27	T
GERP RS		4.5
Varity_R		0.36
gMVP		0.52
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs148168726; hg19: chr7-22999934; COSMIC: COSV69471318;