21-43169134-G-A

Position:

• chr21-43169134-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PM1 PM5 PP3_Strong BS2

The NM_000394.4(CRYAA):​c.35G>A​(p.Arg12His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 961,486 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 11)
  • Exomes 𝑓: 0.000011 (3 hom.)
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.07

Genes affected

CRYAA (HGNC:2388): (crystallin alpha A) 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. Post-translational modifications decrease the ability to chaperone. 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. Defects in this gene cause autosomal dominant congenital cataract (ADCC). [provided by RefSeq, Jan 2014]

CRYAA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a chain Alpha-crystallin A(1-172) (size 171) in uniprot entity CRYAA_HUMAN there are 32 pathogenic changes around while only 0 benign (100%) in NM_000394.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRYAA	NM_000394.4	c.35G>A	p.Arg12His	missense_variant	1/3	ENST00000291554.6	NP_000385.1
LOC107987300	XR_007067885.1	n.546+1903C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CRYAA	ENST00000291554.6	c.35G>A	p.Arg12His	missense_variant	1/3	1	NM_000394.4	ENSP00000291554.2
CRYAA	ENST00000482775.1	n.48G>A		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251314 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135858

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000114 AC: 11 AN: 961486 Hom.: 3 Cov.: 27 AF XY: 0.00000829 AC XY: 4 AN XY: 482690

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000157

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 11

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cataract 9 multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg12 amino acid residue in CRYAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17724170, 19503744, 22045060, 23508780). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This variant has not been reported in the literature in individuals affected with CRYAA-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 12 of the CRYAA protein (p.Arg12His). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.54	P
Vest4		0.75
MutPred		0.91		Gain of catalytic residue at L14 (P = 0.0517);
MVP		0.94
MPC		0.53
ClinPred		0.96	D
GERP RS		4.9
Varity_R		0.65
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs776884812; hg19: chr21-44589244; COSMIC: COSV99374830; COSMIC: COSV99374830;