1-74719225-G-C

Position:

• chr1-74719225-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001889.4(CRYZ):​c.412C>G​(p.Arg138Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYZ NM_001889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYZ	NM_001889.4	c.412C>G	p.Arg138Gly	missense_variant	4/9	ENST00000340866.10	NP_001880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYZ	ENST00000340866.10	c.412C>G	p.Arg138Gly	missense_variant	4/9	1	NM_001889.4	ENSP00000339399.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2024

The c.412C>G (p.R138G) alteration is located in exon 5 (coding exon 3) of the CRYZ gene. This alteration results from a C to G substitution at nucleotide position 412, causing the arginine (R) at amino acid position 138 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.35	T;T;.;T;.
Eigen	Benign	-0.011
Eigen_PC	Benign	-0.014
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;L;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.0	D;D;D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;.;.
Polyphen		0.88	P;P;.;.;.
Vest4		0.80
MutPred		0.67		Loss of methylation at R138 (P = 0.0188);Loss of methylation at R138 (P = 0.0188);Loss of methylation at R138 (P = 0.0188);Loss of methylation at R138 (P = 0.0188);Loss of methylation at R138 (P = 0.0188);
MVP		0.45
MPC		0.58
ClinPred		0.98	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.93
gMVP		0.79

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: rs777653390; hg19: chr1-75184909;