Genetic Variant CRYAB:p.Leu55Leu (chr11-111911560-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001289808.2(CRYAB):c.165G>A(p.Leu55Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,612,794 control chromosomes in the GnomAD database, including 349 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 32)

Exomes 𝑓: 0.019 ( 326 hom. )

Consequence

CRYAB
NM_001289808.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.166

Publications

12 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 11-111911560-C-T is Benign according to our data. Variant chr11-111911560-C-T is described in ClinVar as Benign. ClinVar VariationId is 44233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.166 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0132 (2014/152176) while in subpopulation SAS AF = 0.0239 (115/4812). AF 95% confidence interval is 0.0204. There are 23 homozygotes in GnomAd4. There are 904 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AD,AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
CRYAB	NM_001289808.2	MANE Select	c.165G>A	p.Leu55Leu	synonymous	Exon 1 of 3	NP_001276737.1	P02511
CRYAB	NM_001289807.1		c.165G>A	p.Leu55Leu	synonymous	Exon 2 of 4	NP_001276736.1	P02511
CRYAB	NM_001368245.1		c.165G>A	p.Leu55Leu	synonymous	Exon 2 of 4	NP_001355174.1	P02511

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRYAB	ENST00000650687.2	MANE Select	c.165G>A	p.Leu55Leu	synonymous	Exon 1 of 3	ENSP00000499082.1	P02511
CRYAB	ENST00000526180.6	TSL:1	c.165G>A	p.Leu55Leu	synonymous	Exon 2 of 4	ENSP00000436051.1	P02511
CRYAB	ENST00000227251.7	TSL:5	c.165G>A	p.Leu55Leu	synonymous	Exon 2 of 4	ENSP00000227251.3	P02511

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

2015

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00377

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00885

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0237

Gnomad FIN

AF:

0.0150

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0206

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0154

AC:

3821

AN:

248196

AF XY:

0.0166

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.00458

Gnomad ASJ exome

AF:

0.00691

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.0164

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0151

GnomAD4 exome

AF:

0.0191

AC:

27861

AN:

1460618

Hom.:

326

Cov.:

AF XY:

0.0191

AC XY:

13867

AN XY:

726454

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

33472

American (AMR)

AF:

0.00525

AC:

234

AN:

44554

Ashkenazi Jewish (ASJ)

AF:

0.00591

AC:

154

AN:

26054

East Asian (EAS)

AF:

0.000151

AC:

AN:

39676

South Asian (SAS)

AF:

0.0263

AC:

2260

AN:

85830

European-Finnish (FIN)

AF:

0.0156

AC:

830

AN:

53296

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0210

AC:

23291

AN:

1111612

Other (OTH)

AF:

0.0156

AC:

942

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1610

3220

4831

6441

8051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

854

1708

2562

3416

4270

<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:

0.0132

AC:

2014

AN:

152176

Hom.:

Cov.:

AF XY:

0.0121

AC XY:

904

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.00376

AC:

156

AN:

41510

American (AMR)

AF:

0.00884

AC:

135

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00605

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0239

AC:

115

AN:

4812

European-Finnish (FIN)

AF:

0.0150

AC:

159

AN:

10608

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0205

AC:

1397

AN:

67992

Other (OTH)

AF:

0.0109

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

101

201

302

402

503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0167

Hom.:

Bravo

AF:

0.0119

Asia WGS

AF:

0.00837

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (3)

Cardiovascular phenotype (1)

Cataract 16 multiple types (1)

Dilated cardiomyopathy 1II (1)

Fatal infantile hypertonic myofibrillar myopathy (1)

Myofibrillar Myopathy, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.4

(source)

DANN

Benign

0.85

PhyloP100

0.17

PromoterAI

-0.034

Neutral

(source)

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

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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