21-33613586-C-T

Variant names:

• chr21-33613586-C-T
• NM_145858.3:c.283G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_145858.3(CRYZL1):​c.283G>A​(p.Glu95Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 4.67

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35496813).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYZL1	NM_145858.3	c.283G>A	p.Glu95Lys	missense_variant	Exon 6 of 13	ENST00000381554.8	NP_665857.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYZL1	ENST00000381554.8	c.283G>A	p.Glu95Lys	missense_variant	Exon 6 of 13	1	NM_145858.3	ENSP00000370966.3
CRYZL1	ENST00000381540.7	c.283G>A	p.Glu95Lys	missense_variant	Exon 6 of 13	2		ENSP00000370951.3
ENSG00000249209	ENST00000429238.2	c.442-27405G>A		intron_variant	Intron 6 of 7	5		ENSP00000394107.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.283G>A (p.E95K) alteration is located in exon 6 (coding exon 5) of the CRYZL1 gene. This alteration results from a G to A substitution at nucleotide position 283, causing the glutamic acid (E) at amino acid position 95 to be replaced by a lysine (K). 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	0.071
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;T;T;T;T;T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.066	T;T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;T;T;.;.
Polyphen		0.76	P;.;.;P;.;.;.
Vest4		0.71
MutPred		0.46		Loss of stability (P = 0.0236);.;Loss of stability (P = 0.0236);.;.;Loss of stability (P = 0.0236);.;
MVP		0.66
MPC		0.71
ClinPred		0.90	D
GERP RS		5.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.14
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-34985892;