1-74723167-T-C

Position:

• chr1-74723167-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001889.4(CRYZ):​c.215A>G​(p.Asp72Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D72V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CRYZ NM_001889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.21

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYZ	NM_001889.4	c.215A>G	p.Asp72Gly	missense_variant	3/9	ENST00000340866.10	NP_001880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYZ	ENST00000340866.10	c.215A>G	p.Asp72Gly	missense_variant	3/9	1	NM_001889.4	ENSP00000339399.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Oct 06, 2022

The c.215A>G (p.D72G) alteration is located in exon 4 (coding exon 2) of the CRYZ gene. This alteration results from a A to G substitution at nucleotide position 215, causing the aspartic acid (D) at amino acid position 72 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	0.97
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.2	M;M;M;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.6	D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;.;.
Polyphen		1.0	D;D;.;.;.
Vest4		0.98
MutPred		0.75		Gain of glycosylation at S71 (P = 0.0215);Gain of glycosylation at S71 (P = 0.0215);Gain of glycosylation at S71 (P = 0.0215);Gain of glycosylation at S71 (P = 0.0215);Gain of glycosylation at S71 (P = 0.0215);
MVP		0.53
MPC		0.55
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs771368090; hg19: chr1-75188851;