1-74723218-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001889.4(CRYZ):c.164G>A(p.Arg55His) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,613,930 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: CRYZ NM_001889.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.11

Genes affected

CRYZ (HGNC:2419): (crystallin zeta) Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. The former class is also called phylogenetically-restricted crystallins. This gene encodes a taxon-specific crystallin protein which has NADPH-dependent quinone reductase activity distinct from other known quinone reductases. It lacks alcohol dehydrogenase activity although by similarity it is considered a member of the zinc-containing alcohol dehydrogenase family. Unlike other mammalian species, in humans, lens expression is low. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. One pseudogene is known to exist. [provided by RefSeq, Sep 2008]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16012505).
• BP6: Variant 1-74723218-C-T is Benign according to our data. Variant chr1-74723218-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2214695.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYZ	NM_001889.4	c.164G>A	p.Arg55His	missense_variant	3/9	ENST00000340866.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYZ	ENST00000340866.10	c.164G>A	p.Arg55His	missense_variant	3/9	1	NM_001889.4	P1

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 159 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000696 AC: 175 AN: 251300 Hom.: 0 AF XY: 0.000626 AC XY: 85 AN XY: 135828

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00121

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00126 AC: 1849 AN: 1461702 Hom.: 2 Cov.: 31 AF XY: 0.00125 AC XY: 911 AN XY: 727174

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00154

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.000967 AC XY: 72 AN XY: 74436

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.00119

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.000684 AC: 83

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2022

The c.164G>A (p.R55H) alteration is located in exon 4 (coding exon 2) of the CRYZ gene. This alteration results from a G to A substitution at nucleotide position 164, causing the arginine (R) at amino acid position 55 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CRYZ-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.4	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;D
REVEL	Uncertain	0.51
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.90
MVP		0.48
MPC		0.53
ClinPred		0.69	D
GERP RS		4.5
Varity_R		0.82
gMVP		0.90

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: rs140443058; hg19: chr1-75188902;