11-111910113-G-A

Variant names:

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+214C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 709,950 control chromosomes in the GnomAD database, including 27,418 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5655 hom., cov: 32)

Exomes 𝑓: 0.28 ( 21763 hom. )

Consequence

CRYAB
NM_001289808.2 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.36

Publications

15 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 (BayesDel_noAF=-0.76).

BP6

Variant 11-111910113-G-A is Benign according to our data. Variant chr11-111910113-G-A is described in ClinVar as Benign. ClinVar VariationId is 672477.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+214C>T	intron	N/A	NP_001276737.1	P02511
CRYAB	NM_001289807.1		c.324+214C>T	intron	N/A	NP_001276736.1	P02511
CRYAB	NM_001368245.1		c.324+214C>T	intron	N/A	NP_001355174.1	P02511

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CRYAB	ENST00000650687.2	MANE Select	c.324+214C>T	intron	N/A	ENSP00000499082.1	P02511
CRYAB	ENST00000526180.6	TSL:1	c.324+214C>T	intron	N/A	ENSP00000436051.1	P02511
CRYAB	ENST00000533971.2	TSL:2	c.*70C>T	3_prime_UTR	Exon 3 of 3	ENSP00000434269.1	E9PRA8

Frequencies

GnomAD3 genomes

AF:

0.268

AC:

40713

AN:

151896

Hom.:

5659

Cov.:

show subpopulations

Gnomad AFR

AF:

0.221

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.343

Gnomad ASJ

AF:

0.363

Gnomad EAS

AF:

0.180

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.305

GnomAD4 exome

AF:

0.277

AC:

154587

AN:

557938

Hom.:

21763

Cov.:

AF XY:

0.277

AC XY:

83335

AN XY:

300556

show subpopulations

African (AFR)

AF:

0.216

AC:

3456

AN:

15970

American (AMR)

AF:

0.303

AC:

10351

AN:

34154

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

6943

AN:

19470

East Asian (EAS)

AF:

0.187

AC:

5990

AN:

31986

South Asian (SAS)

AF:

0.258

AC:

15784

AN:

61266

European-Finnish (FIN)

AF:

0.244

AC:

8058

AN:

32972

Middle Eastern (MID)

AF:

0.331

AC:

1249

AN:

3778

European-Non Finnish (NFE)

AF:

0.286

AC:

93858

AN:

327688

Other (OTH)

AF:

0.290

AC:

8898

AN:

30654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

6214

12428

18643

24857

31071

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

648

1296

1944

2592

3240

<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:

40711

AN:

152012

Hom.:

5655

Cov.:

AF XY:

0.268

AC XY:

19900

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.221

AC:

9138

AN:

41430

American (AMR)

AF:

0.342

AC:

5227

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.363

AC:

1260

AN:

3468

East Asian (EAS)

AF:

0.180

AC:

933

AN:

5174

South Asian (SAS)

AF:

0.244

AC:

1178

AN:

4824

European-Finnish (FIN)

AF:

0.256

AC:

2707

AN:

10554

Middle Eastern (MID)

AF:

0.299

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.285

AC:

19388

AN:

67968

Other (OTH)

AF:

0.301

AC:

635

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1487

2975

4462

5950

7437

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:

0.247

Hom.:

1885

Bravo

AF:

0.271

Asia WGS

AF:

0.227

AC:

791

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

5.5

(source)

DANN

Benign

0.67

PhyloP100

1.4

Mutation Taster

=100/0

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

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