NM_015974.3:c.875C>T

Variant names:

• chr13-20404214-G-A
• rs372602783
• NM_015974.3:c.875C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_015974.3(CRYL1):​c.875C>T​(p.Pro292Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000075 in 1,613,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: CRYL1 NM_015974.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.02
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039896697).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015974.3. 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
	CRYL1	NM_015974.3	MANE Select	c.875C>T	p.Pro292Leu	missense	Exon 8 of 8	NP_057058.2	Q9Y2S2-1
	CRYL1	NM_001363647.2		c.713C>T	p.Pro238Leu	missense	Exon 7 of 7	NP_001350576.1	A0A2R8Y4K2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYL1	ENST00000298248.12	TSL:1 MANE Select	c.875C>T	p.Pro292Leu	missense	Exon 8 of 8	ENSP00000298248.7	Q9Y2S2-1
	CRYL1	ENST00000382812.5	TSL:1	c.809C>T	p.Pro270Leu	missense	Exon 9 of 9	ENSP00000372262.1	Q9Y2S2-2
	CRYL1	ENST00000887623.1		c.836C>T	p.Pro279Leu	missense	Exon 8 of 8	ENSP00000557682.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000442 AC: 11 AN: 248906 AF XY: 0.0000444

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000630 AC: 92 AN: 1461220 Hom.: 0 Cov.: 30 AF XY: 0.0000591 AC XY: 43 AN XY: 726980

African (AFR) AF: 0.000598 AC: 20 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111478

Other (OTH) AF: 0.0000662 AC: 4 AN: 60380

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74416

African (AFR) AF: 0.000674 AC: 28 AN: 41514

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.000204

ESP6500AA AF: 0.000253 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000496 AC: 6

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Benign	0.85
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.091
Sift	Benign	0.79	T
Sift4G	Benign	0.41	T
Polyphen		0.94	P
Vest4		0.42
MVP		0.57
MPC		0.35
ClinPred		0.13	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.67
Mutation Taster		=72/28	polymorphism

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

Other links and lift over

dbSNP: rs372602783; hg19: chr13-20978353;