chr21-33621997-A-G

Variant names:

• chr21-33621997-A-G
• rs139699692
• NM_145858.3:c.216T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_145858.3(CRYZL1):​c.216T>C​(p.Asp72Asp) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,754 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CRYZL1 NM_145858.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001516
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.032).
• BP7: Synonymous conserved (PhyloP=-0.021 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145858.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYZL1	NM_145858.3	MANE Select	c.216T>C	p.Asp72Asp	splice_region synonymous	Exon 4 of 13	NP_665857.2	O95825-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYZL1	ENST00000381554.8	TSL:1 MANE Select	c.216T>C	p.Asp72Asp	splice_region synonymous	Exon 4 of 13	ENSP00000370966.3	O95825-1
	CRYZL1	ENST00000361534.6	TSL:1	c.288T>C	p.Asp96Asp	splice_region synonymous	Exon 5 of 13	ENSP00000355075.2	A6NHJ8
	CRYZL1	ENST00000381540.7	TSL:2	c.216T>C	p.Asp72Asp	splice_region synonymous	Exon 4 of 13	ENSP00000370951.3	A6NND8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444754 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 719954

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33108

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39456

South Asian (SAS) AF: 0.00 AC: 0 AN: 85824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.12e-7 AC: 1 AN: 1096732

Other (OTH) AF: 0.00 AC: 0 AN: 59818

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.5
DANN	Benign	0.88
PhyloP100		-0.021
PromoterAI		0.0050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs139699692; hg19: chr21-34994303;