Variant 13-20404724-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015974.3(CRYL1):c.757G>A(p.Asp253Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,612,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CRYL1
NM_015974.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 2.25

Variant links:

Genes affected

CRYL1 (HGNC:18246): (crystallin lambda 1) The uronate cycle functions as an alternative glucose metabolic pathway, accounting for about 5% of daily glucose catabolism. The product of this gene catalyzes the dehydrogenation of L-gulonate into dehydro-L-gulonate in the uronate cycle. The enzyme requires NAD(H) as a coenzyme, and is inhibited by inorganic phosphate. A similar gene in the rabbit is thought to serve a structural role in the lens of the eye. [provided by RefSeq, Jul 2008]

CRYL1 links:

CRYL1 (HGNC:):

CRYL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.027471304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYL1	NM_015974.3 linkuse as main transcript	c.757G>A	p.Asp253Asn	missense_variant	7/8	ENST00000298248.12	NP_057058.2	Q9Y2S2-1V9HWG2
CRYL1	NM_001363647.2 linkuse as main transcript	c.595G>A	p.Asp199Asn	missense_variant	6/7		NP_001350576.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYL1	ENST00000298248.12 linkuse as main transcript	c.757G>A	p.Asp253Asn	missense_variant	7/8	1	NM_015974.3	ENSP00000298248.7		Q9Y2S2-1

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000289

AC:

AN:

249350

Hom.:

AF XY:

0.000266

AC XY:

AN XY:

135300

show subpopulations

Gnomad AFR exome

AF:

0.00181

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00228

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000972

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000157

AC:

229

AN:

1460300

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

108

AN XY:

726590

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00344

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000270

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000841

AC:

128

AN:

152178

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00251

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.000365

Hom.:

Bravo

AF:

0.00110

ESP6500AA

AF:

0.00188

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000240

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 11, 2021

The c.757G>A (p.D253N) alteration is located in exon 7 (coding exon 7) of the CRYL1 gene. This alteration results from a G to A substitution at nucleotide position 757, causing the aspartic acid (D) at amino acid position 253 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CRYL1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 05, 2020

This variant is classified as likely 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

0.11

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.11

T;.;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.88

D;D;.;D

M_CAP

Benign

0.076

MetaRNN

Benign

0.027

T;T;T;T

MetaSVM

Uncertain

-0.028

MutationAssessor

Benign

1.3

L;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.8

N;.;N;.

REVEL

Benign

0.25

Sift

Benign

0.26

T;.;T;.

Sift4G

Benign

0.24

T;.;T;.

Polyphen

0.010

B;.;.;.

Vest4

0.41

MVP

0.80

MPC

0.20

ClinPred

0.011

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.36

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over