rs11603779

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001289808.2(CRYAB):c.324+4T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,613,724 control chromosomes in the GnomAD database, including 64,777 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5663 hom., cov: 32)

Exomes 𝑓: 0.28 ( 59114 hom. )

Consequence

CRYAB
NM_001289808.2 splice_region, intron

Scores

Splicing: ADA: 0.00003259

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.714

Publications

24 publications found

Variant links:

Genes affected

CRYAB (HGNC:2389): (crystallin alpha B) Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2019]

CRYAB Gene-Disease associations (from GenCC):

myofibrillar myopathy 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
cataract 16 multiple types
Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
fatal infantile hypertonic myofibrillar myopathy
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
early-onset lamellar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset posterior polar cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy 1II
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CRYAB 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=0.0039369464).

BP6

Variant 11-111910323-A-C is Benign according to our data. Variant chr11-111910323-A-C is described in ClinVar as Benign. ClinVar VariationId is 44234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001289808.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CRYAB	NM_001289808.2	MANE Select	c.324+4T>G	splice_region intron	N/A	NP_001276737.1	P02511
CRYAB	NM_001289807.1		c.324+4T>G	splice_region intron	N/A	NP_001276736.1	P02511
CRYAB	NM_001368245.1		c.324+4T>G	splice_region intron	N/A	NP_001355174.1	P02511

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRYAB	ENST00000650687.2	MANE Select	c.324+4T>G		splice_region intron	N/A	ENSP00000499082.1	P02511
CRYAB	ENST00000526180.6	TSL:1	c.324+4T>G		splice_region intron	N/A	ENSP00000436051.1	P02511
CRYAB	ENST00000533971.2	TSL:2	c.328T>G	p.Cys110Gly	missense	Exon 3 of 3	ENSP00000434269.1	E9PRA8

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40773

AN:

151948

Hom.:

5665

Cov.:

show subpopulations

Gnomad AFR

AF:

0.222

Gnomad AMI

AF:

0.172

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.180

Gnomad SAS

AF:

0.246

Gnomad FIN

AF:

0.255

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.304

GnomAD2 exomes

AF:

0.274

AC:

68923

AN:

251388

AF XY:

0.277

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.300

Gnomad ASJ exome

AF:

0.360

Gnomad EAS exome

AF:

0.178

Gnomad FIN exome

AF:

0.255

Gnomad NFE exome

AF:

0.290

Gnomad OTH exome

AF:

0.295

GnomAD4 exome

AF:

0.282

AC:

412753

AN:

1461658

Hom.:

59114

Cov.:

AF XY:

0.282

AC XY:

205345

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.215

AC:

7210

AN:

33480

American (AMR)

AF:

0.300

AC:

13435

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.358

AC:

9351

AN:

26136

East Asian (EAS)

AF:

0.188

AC:

7468

AN:

39700

South Asian (SAS)

AF:

0.259

AC:

22310

AN:

86254

European-Finnish (FIN)

AF:

0.248

AC:

13216

AN:

53372

Middle Eastern (MID)

AF:

0.326

AC:

1880

AN:

5768

European-Non Finnish (NFE)

AF:

0.288

AC:

320557

AN:

1111832

Other (OTH)

AF:

0.287

AC:

17326

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

17384

34767

52151

69534

86918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10636

21272

31908

42544

53180

<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:

0.268

AC:

40778

AN:

152066

Hom.:

5663

Cov.:

AF XY:

0.268

AC XY:

19914

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.222

AC:

9205

AN:

41466

American (AMR)

AF:

0.342

AC:

5221

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.364

AC:

1260

AN:

3466

East Asian (EAS)

AF:

0.180

AC:

932

AN:

5182

South Asian (SAS)

AF:

0.245

AC:

1180

AN:

4818

European-Finnish (FIN)

AF:

0.255

AC:

2691

AN:

10548

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.285

AC:

19407

AN:

67992

Other (OTH)

AF:

0.301

AC:

636

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1531

3061

4592

6122

7653

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

424

848

1272

1696

2120

<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:

0.279

Hom.:

8959

Bravo

AF:

0.271

TwinsUK

AF:

0.289

AC:

1070

ALSPAC

AF:

0.303

AC:

1169

ESP6500AA

AF:

0.219

AC:

962

ESP6500EA

AF:

0.300

AC:

2578

ExAC

AF:

0.270

AC:

32718

Asia WGS

AF:

0.229

AC:

796

AN:

3478

EpiCase

AF:

0.311

EpiControl

AF:

0.302

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (9)

Cataract 16 multiple types (2)

Fatal infantile hypertonic myofibrillar myopathy (2)

Cardiovascular phenotype (1)

Dilated cardiomyopathy 1II (1)

Myofibrillar myopathy 2 (1)

Myofibrillar Myopathy, Dominant (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

1.1

(source)

DANN

Benign

0.51

DEOGEN2

Benign

0.0069

Eigen

Benign

-0.99

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.21

MetaRNN

Benign

0.0039

MetaSVM

Benign

-1.0

PhyloP100

-0.71

PROVEAN

Benign

2.1

REVEL

Benign

0.15

Sift

Benign

0.43

Sift4G

Benign

0.60

Polyphen

0.0

Vest4

0.16

ClinPred

0.0037

GERP RS

-6.7

PromoterAI

-0.021

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000033

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

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

Computational scores

Splicing

Publications

Other links and lift over