1-26324310-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001039775.4(CRYBG2):c.4579C>T(p.Arg1527Cys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000418 in 1,602,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1527H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

CRYBG2
NM_001039775.4 missense, splice_region

Scores

Splicing: ADA: 0.9937

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.79

Variant links:

Genes affected

CRYBG2 (HGNC:17295): (crystallin beta-gamma domain containing 2) Predicted to enable carbohydrate binding activity. [provided by Alliance of Genome Resources, Apr 2022]

CRYBG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.745

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYBG2	NM_001039775.4 link	c.4579C>T	p.Arg1527Cys	missense_variant, splice_region_variant	Exon 18 of 20	ENST00000308182.10	NP_001034864.2	Q8N1P7Q9NWG5
CRYBG2	XM_011541673.3 link	c.4750C>T	p.Arg1584Cys	missense_variant, splice_region_variant	Exon 18 of 20		XP_011539975.1
CRYBG2	XM_005245918.3 link	c.4579C>T	p.Arg1527Cys	missense_variant, splice_region_variant	Exon 18 of 20		XP_005245975.1	Q8N1P7
CRYBG2	XM_011541672.2 link	c.4543C>T	p.Arg1515Cys	missense_variant, splice_region_variant	Exon 17 of 19		XP_011539974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRYBG2	ENST00000308182.10 link	c.4579C>T	p.Arg1527Cys	missense_variant, splice_region_variant	Exon 18 of 20	5	NM_001039775.4	ENSP00000310435.6	Q8N1P7
CRYBG2	ENST00000475866.3 link	c.5551C>T	p.Arg1851Cys	missense_variant, splice_region_variant	Exon 20 of 22	4		ENSP00000428746.2	E7ET48
CRYBG2	ENST00000374208.1 link	n.57C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	5
CRYBG2	ENST00000374211.5 link	n.193C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000154

AC:

AN:

240382

Hom.:

AF XY:

0.000123

AC XY:

AN XY:

130548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000177

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000448

AC:

AN:

1450500

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

721478

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000656

Gnomad4 NFE exome

AF:

0.0000424

Gnomad4 OTH exome

AF:

0.0000998

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4579C>T (p.R1527C) alteration is located in exon 18 (coding exon 17) of the AIM1L gene. This alteration results from a C to T substitution at nucleotide position 4579, causing the arginine (R) at amino acid position 1527 to be replaced by a cysteine (C). 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

0.22

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.75

D;D;D

MetaSVM

Uncertain

-0.064

PrimateAI

Uncertain

0.69

REVEL

Uncertain

0.62

Sift4G

Pathogenic

0.0

.;D;.

Vest4

0.68

MVP

0.80

MPC

0.99

ClinPred

0.76

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.90

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