rs61751949

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020989.4(CRYGC):c.143G>A(p.Arg48His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,614,176 control chromosomes in the GnomAD database, including 365 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R48C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.012 ( 19 hom., cov: 33)

Exomes 𝑓: 0.017 ( 346 hom. )

Consequence

CRYGC
NM_020989.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.12

Publications

21 publications found

Variant links:

Genes affected

CRYGC (HGNC:2410): (crystallin gamma C) This gene encodes a member of the beta/gamma-crystallin family of proteins. Crystallins constitute the major proteins of vertebrate eye lens and maintain the transparency and refractive index of the lens. This gene and several family members are present in a gene cluster on chromosome 2. Mutations in this gene have been shown to cause multiple types of cataract, including Coppock-like cataract and zonular pulverulent cataract, among others. [provided by RefSeq, Jan 2015]

CRYGC Gene-Disease associations (from GenCC):

cataract 2, multiple types
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
cataract - microcornea syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pulverulent cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CRYGC links:

ENSG00000295187 (HGNC:):

ENSG00000295187 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005558312).

BP6

Variant 2-208129550-C-T is Benign according to our data. Variant chr2-208129550-C-T is described in ClinVar as Benign. ClinVar VariationId is 402565.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0117 (1776/152284) while in subpopulation SAS AF = 0.0483 (233/4822). AF 95% confidence interval is 0.0432. There are 19 homozygotes in GnomAd4. There are 861 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1776 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020989.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYGC	NM_020989.4	MANE Select	c.143G>A	p.Arg48His	missense	Exon 2 of 3	NP_066269.1
	LOC100507443	NR_038437.1		n.98-7506C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CRYGC	ENST00000282141.4	TSL:1 MANE Select	c.143G>A	p.Arg48His	missense	Exon 2 of 3	ENSP00000282141.3
ENSG00000295187	ENST00000728538.1		n.101-7506C>T		intron	N/A
ENSG00000295187	ENST00000728539.1		n.118-7506C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1775

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0481

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.0168

AC:

4221

AN:

251486

AF XY:

0.0189

show subpopulations

Gnomad AFR exome

AF:

0.00308

Gnomad AMR exome

AF:

0.00633

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0165

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0175

AC:

25556

AN:

1461892

Hom.:

346

Cov.:

AF XY:

0.0184

AC XY:

13370

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33480

American (AMR)

AF:

0.00669

AC:

299

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00348

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0511

AC:

4406

AN:

86258

European-Finnish (FIN)

AF:

0.0175

AC:

935

AN:

53420

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0168

AC:

18694

AN:

1112012

Other (OTH)

AF:

0.0160

AC:

966

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

1564

3128

4692

6256

7820

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

738

1476

2214

2952

3690

<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:

0.0117

AC:

1776

AN:

152284

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

861

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41562

American (AMR)

AF:

0.00693

AC:

106

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5182

South Asian (SAS)

AF:

0.0483

AC:

233

AN:

4822

European-Finnish (FIN)

AF:

0.0161

AC:

171

AN:

10602

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0161

AC:

1092

AN:

68028

Other (OTH)

AF:

0.0137

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

174

261

348

435

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0140

Hom.:

Bravo

AF:

0.00961

TwinsUK

AF:

0.0165

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0147

AC:

126

ExAC

AF:

0.0174

AC:

2112

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0149

EpiControl

AF:

0.0148

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Nuclear pulverulent cataract (1)

Usher syndrome type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.12

MetaRNN

Benign

0.0056

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.0

PhyloP100

1.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

REVEL

Benign

0.11

Sift

Benign

0.26

Sift4G

Benign

0.70

Polyphen

0.12

Vest4

0.083

MPC

0.13

ClinPred

0.012

GERP RS

1.1

PromoterAI

-0.050

Neutral

(source)

Varity_R

0.11

gMVP

0.39

Mutation Taster

=87/13

polymorphism (auto)

(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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over