1-74710181-C-T

Position:

• chr1-74710181-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001889.4(CRYZ):​c.547G>A​(p.Glu183Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,613,862 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.017 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (64 hom.)
• Consequence: CRYZ NM_001889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.80

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002904147).
• BP6: Variant 1-74710181-C-T is Benign according to our data. Variant chr1-74710181-C-T is described in ClinVar as [Benign]. Clinvar id is 783288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYZ	NM_001889.4	c.547G>A	p.Glu183Lys	missense_variant	6/9	ENST00000340866.10	NP_001880.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYZ	ENST00000340866.10	c.547G>A	p.Glu183Lys	missense_variant	6/9	1	NM_001889.4	ENSP00000339399.5

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2661 AN: 152172 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0614

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00426 AC: 1070 AN: 251118 Hom.: 23 AF XY: 0.00326 AC XY: 443 AN XY: 135706

Gnomad AFR exome AF: 0.0590

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00168 AC: 2453 AN: 1461572 Hom.: 64 Cov.: 31 AF XY: 0.00145 AC XY: 1053 AN XY: 727080

Gnomad4 AFR exome AF: 0.0600

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0175 AC: 2662 AN: 152290 Hom.: 71 Cov.: 33 AF XY: 0.0173 AC XY: 1286 AN XY: 74468

Gnomad4 AFR AF: 0.0612

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00366 Hom.: 29

Bravo AF: 0.0196

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0554 AC: 244

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00535 AC: 649

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

CRYZ-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2019

This variant is classified as 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	Benign	0.072
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.85
DEOGEN2	Benign	0.056	.;T;T;.;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;.;D;D;D;D
MetaRNN	Benign	0.0029	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	.;M;M;M;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.19	T;T;T;T;T;T
Sift4G	Benign	0.67	T;T;T;T;.;.
Polyphen		0.029	.;B;B;.;.;.
Vest4		0.26
MVP		0.50
MPC		0.11
ClinPred		0.018	T
GERP RS		4.6
Varity_R		0.35
gMVP		0.45

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: rs17095822; hg19: chr1-75175865;