chr11-111911573-G-C

Variant names:

• chr11-111911573-G-C
• NM_001289808.2:c.152C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001289808.2(CRYAB):​c.152C>G​(p.Pro51Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P51L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRYAB NM_001289808.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.509

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17520502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAB	NM_001289808.2	c.152C>G	p.Pro51Arg	missense_variant	Exon 1 of 3	ENST00000650687.2	NP_001276737.1
CRYAB	NM_001289807.1	c.152C>G	p.Pro51Arg	missense_variant	Exon 2 of 4		NP_001276736.1
CRYAB	NM_001368245.1	c.152C>G	p.Pro51Arg	missense_variant	Exon 2 of 4		NP_001355174.1
CRYAB	NM_001885.3	c.152C>G	p.Pro51Arg	missense_variant	Exon 2 of 4		NP_001876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAB	ENST00000650687.2	c.152C>G	p.Pro51Arg	missense_variant	Exon 1 of 3		NM_001289808.2	ENSP00000499082.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	9.4
DANN	Benign	0.81
DEOGEN2	Benign	0.38	T;T;T;T;T;T;T;T;T;T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.28	.;T;.;.;.;.;.;T;T;T;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.90	L;L;L;L;L;L;.;.;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.33	N;.;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.17	T;.;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T;T;.;.;T;.;.
Polyphen		0.0	B;B;B;B;B;B;.;.;B;.;.
Vest4		0.11
MutPred		0.57		Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);Loss of catalytic residue at P51 (P = 0.0422);
MVP		0.83
MPC		0.41
ClinPred		0.053	T
GERP RS		-0.89
Varity_R		0.11
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-111782297;