rs4252583

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000526180.6(CRYAB):c.-224-150C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 275,266 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.012 ( 34 hom., cov: 32)

Exomes 𝑓: 0.0028 ( 4 hom. )

Consequence

CRYAB
ENST00000526180.6 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.02

Publications

1 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: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
fatal infantile hypertonic myofibrillar myopathy
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 11-111912098-G-A is Benign according to our data. Variant chr11-111912098-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1207966.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0123 (1869/152238) while in subpopulation AFR AF = 0.0396 (1643/41510). AF 95% confidence interval is 0.038. There are 34 homozygotes in GnomAd4. There are 861 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
CRYAB	NM_001289807.1 link	c.-198-176C>T	intron_variant	Intron 1 of 3	NP_001276736.1	P02511V9HW27
CRYAB	NM_001368245.1 link	c.-198-176C>T	intron_variant	Intron 1 of 3	NP_001355174.1
CRYAB	NM_001885.3 link	c.-198-176C>T	intron_variant	Intron 1 of 3	NP_001876.1	P02511V9HW27

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
CRYAB	ENST00000526180.6 link	c.-224-150C>T	intron_variant	Intron 1 of 3	1	ENSP00000436051.1	P02511
CRYAB	ENST00000527899.6 link	c.-198-176C>T	intron_variant	Intron 1 of 3	2	ENSP00000436089.2	P02511
CRYAB	ENST00000527950.5 link	c.-198-176C>T	intron_variant	Intron 1 of 3	5	ENSP00000437149.1	P02511

Frequencies

GnomAD3 genomes

AF:

0.0123

AC:

1867

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0396

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00923

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.000750

Gnomad OTH

AF:

0.00957

GnomAD4 exome

AF:

0.00276

AC:

339

AN:

123028

Hom.:

Cov.:

AF XY:

0.00231

AC XY:

149

AN XY:

64590

show subpopulations

African (AFR)

AF:

0.0379

AC:

184

AN:

4856

American (AMR)

AF:

0.00665

AC:

AN:

6316

Ashkenazi Jewish (ASJ)

AF:

0.00208

AC:

AN:

3370

East Asian (EAS)

AF:

0.000285

AC:

AN:

7016

South Asian (SAS)

AF:

0.00

AC:

AN:

16362

European-Finnish (FIN)

AF:

0.000219

AC:

AN:

4562

Middle Eastern (MID)

AF:

0.0120

AC:

AN:

498

European-Non Finnish (NFE)

AF:

0.000939

AC:

AN:

73492

Other (OTH)

AF:

0.00427

AC:

AN:

6556

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.0123

AC:

1869

AN:

152238

Hom.:

Cov.:

AF XY:

0.0116

AC XY:

861

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0396

AC:

1643

AN:

41510

American (AMR)

AF:

0.00922

AC:

141

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000750

AC:

AN:

68020

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

181

272

362

453

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0107

Hom.:

Bravo

AF:

0.0148

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 26, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.9

(source)

DANN

Benign

0.32

PhyloP100

1.0

PromoterAI

-0.31

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over