21-33603436-C-T

Variant names:

• chr21-33603436-C-T
• rs2086776497
• NM_145858.3:c.433G>A

Variant summary

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

The NM_145858.3(CRYZL1):​c.433G>A​(p.Gly145Arg) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYZL1 NM_145858.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

Genes affected

CRYZL1 (HGNC:2420): (crystallin zeta like 1) This gene encodes a protein that has sequence similarity to zeta crystallin, also known as quinone oxidoreductase. This zeta crystallin-like protein also contains an NAD(P)H binding site. Alternatively spliced transcript variants have been observed but their full-length nature has not been completely determined. [provided by RefSeq, Jul 2008]

ENSG00000249209 (HGNC:):

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, 0.912

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYZL1	NM_145858.3	c.433G>A	p.Gly145Arg	missense_variant	Exon 7 of 13	ENST00000381554.8	NP_665857.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYZL1	ENST00000381554.8	c.433G>A	p.Gly145Arg	missense_variant	Exon 7 of 13	1	NM_145858.3	ENSP00000370966.3
CRYZL1	ENST00000381540.7	c.433G>A	p.Gly145Arg	missense_variant	Exon 7 of 13	2		ENSP00000370951.3
ENSG00000249209	ENST00000429238.2	c.442-17255G>A		intron_variant	Intron 6 of 7	5		ENSP00000394107.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.433G>A (p.G145R) alteration is located in exon 7 (coding exon 6) of the CRYZL1 gene. This alteration results from a G to A substitution at nucleotide position 433, causing the glycine (G) at amino acid position 145 to be replaced by an arginine (R). 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	Benign	0.22
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.12	T;T;T;T;T;T;T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;.;.
Polyphen		1.0	D;.;.;.;D;.;.;.;.
Vest4		0.57
MutPred		0.80		Gain of solvent accessibility (P = 0.006);.;Gain of solvent accessibility (P = 0.006);.;.;.;.;Gain of solvent accessibility (P = 0.006);.;
MVP		0.61
MPC		0.30
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.33		Position offset: -32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2086776497; hg19: chr21-34975742;