chr21-33621998-T-C

Variant names:

• chr21-33621998-T-C
• rs1039788469
• NM_145858.3:c.215A>G

Variant summary

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

The NM_145858.3(CRYZL1):​c.215A>G​(p.Asp72Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000138 in 1,446,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CRYZL1 NM_145858.3 missense, splice_region
• Scores: Splicing: ADA: 0.01726
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59

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=0.28285426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYZL1	NM_145858.3	c.215A>G	p.Asp72Gly	missense_variant, splice_region_variant	Exon 4 of 13	ENST00000381554.8	NP_665857.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYZL1	ENST00000381554.8	c.215A>G	p.Asp72Gly	missense_variant, splice_region_variant	Exon 4 of 13	1	NM_145858.3	ENSP00000370966.3
CRYZL1	ENST00000381540.7	c.215A>G	p.Asp72Gly	missense_variant, splice_region_variant	Exon 4 of 13	2		ENSP00000370951.3
ENSG00000249209	ENST00000429238.2	c.442-35817A>G		intron_variant	Intron 6 of 7	5		ENSP00000394107.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251100 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446218 Hom.: 0 Cov.: 27 AF XY: 0.00000278 AC XY: 2 AN XY: 720550

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.215A>G (p.D72G) alteration is located in exon 4 (coding exon 3) of the CRYZL1 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	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T;T;T;T;T;T;T;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.0055
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;T;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.28	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.2	N;N;N;N;N;N;N;N;N
REVEL	Benign	0.096
Sift	Benign	0.060	T;D;T;D;T;D;D;D;D
Sift4G	Benign	0.094	T;D;D;D;D;D;.;.;D
Polyphen		0.074	B;.;B;.;B;.;.;.;.
Vest4		0.39
MutPred		0.64		Gain of catalytic residue at V73 (P = 0.0533);Gain of catalytic residue at V73 (P = 0.0533);Gain of catalytic residue at V73 (P = 0.0533);Gain of catalytic residue at V73 (P = 0.0533);.;.;Gain of catalytic residue at V73 (P = 0.0533);.;Gain of catalytic residue at V73 (P = 0.0533);
MVP		0.56
MPC		0.75
ClinPred		0.53	D
GERP RS		4.3
Varity_R		0.13
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.017
dbscSNV1_RF	Benign	0.24
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: rs1039788469; hg19: chr21-34994304;