Genetic Variant NM_001039775.4:c.4669G>C (chr1-26324220-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001039775.4(CRYBG2):c.4669G>C(p.Val1557Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,250 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

CRYBG2
NM_001039775.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.23

Publications

4 publications found

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 was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018718004).

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001039775.4. 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
	CRYBG2	NM_001039775.4	MANE Select	c.4669G>C	p.Val1557Leu	missense	Exon 18 of 20	NP_001034864.2	Q8N1P7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRYBG2	ENST00000308182.10	TSL:5 MANE Select	c.4669G>C	p.Val1557Leu	missense	Exon 18 of 20	ENSP00000310435.6	Q8N1P7
CRYBG2	ENST00000475866.3	TSL:4	c.5641G>C	p.Val1881Leu	missense	Exon 20 of 22	ENSP00000428746.2	E7ET48
CRYBG2	ENST00000374208.1	TSL:5	n.147G>C		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.00115

AC:

175

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00182

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00115

AC:

287

AN:

250478

AF XY:

0.00122

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000694

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00144

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00153

AC:

2232

AN:

1461016

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

1143

AN XY:

726856

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000805

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00105

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00150

AC:

AN:

52596

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00174

AC:

1939

AN:

1111974

Other (OTH)

AF:

0.00129

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

131

262

393

524

655

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00115

AC:

175

AN:

152234

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41516

American (AMR)

AF:

0.00170

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00182

AC:

124

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00142

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00131

AC:

159

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00172

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.69

Eigen

Benign

-0.12

Eigen_PC

Benign

0.050

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

M_CAP

Benign

0.010

MetaRNN

Benign

0.019

MetaSVM

Benign

-1.1

PhyloP100

3.2

PrimateAI

Uncertain

0.65

REVEL

Benign

0.078

Sift4G

Benign

0.20

Vest4

0.35

MVP

0.53

MPC

0.74

ClinPred

0.022

GERP RS

5.3

gMVP

0.54

Mutation Taster

=85/15

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over