chr11-111911609-G-A

Variant names:

• chr11-111911609-G-A
• rs149787233
• NM_001289808.2:c.116C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001289808.2(CRYAB):​c.116C>T​(p.Pro39Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000189 in 1,612,866 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P39S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: CRYAB NM_001289808.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:3
• Conservation: PhyloP100: 6.14
• Publications: 8 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAB	NM_001289808.2	MANE Select	c.116C>T	p.Pro39Leu	missense	Exon 1 of 3	NP_001276737.1
	CRYAB	NM_001289807.1		c.116C>T	p.Pro39Leu	missense	Exon 2 of 4	NP_001276736.1
	CRYAB	NM_001368245.1		c.116C>T	p.Pro39Leu	missense	Exon 2 of 4	NP_001355174.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAB	ENST00000650687.2	MANE Select	c.116C>T	p.Pro39Leu	missense	Exon 1 of 3	ENSP00000499082.1
	CRYAB	ENST00000526180.6	TSL:1	c.116C>T	p.Pro39Leu	missense	Exon 2 of 4	ENSP00000436051.1
	CRYAB	ENST00000227251.7	TSL:5	c.116C>T	p.Pro39Leu	missense	Exon 2 of 4	ENSP00000227251.3

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000242 AC: 60 AN: 248140 AF XY: 0.000216

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000472

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000190 AC: 277 AN: 1460788 Hom.: 0 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 726544

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26088

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85874

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000222 AC: 247 AN: 1111664

Other (OTH) AF: 0.000182 AC: 11 AN: 60356

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74272

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000384 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000272 AC: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	3	-	not specified (3)
-	2	-	Dilated cardiomyopathy 1II (2)
-	2	-	Myofibrillar myopathy 2;C3554649:Dilated cardiomyopathy 1II;C3808377:Cataract 16 multiple types;C5190691:Fatal infantile hypertonic myofibrillar myopathy (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Cataract 16 multiple types (1)
-	1	-	Fatal infantile hypertonic myofibrillar myopathy (1)
-	-	1	Myofibrillar myopathy 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.9	L
PhyloP100		6.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.20
MVP		0.98
MPC		0.91
ClinPred		0.62	D
GERP RS		5.1
PromoterAI		0.0074	Neutral
Varity_R		0.91
gMVP		0.61
Mutation Taster		=55/45	polymorphism

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

Other links and lift over

dbSNP: rs149787233; hg19: chr11-111782333;