rs776884812

Variant names:

• chr21-43169134-G-A
• rs776884812
• NM_000394.4:c.35G>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 9P and 4B. PM1 PM5 PP2 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. R12C) 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]

LOC107987300 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a chain Alpha-crystallin A chain (size 172) in uniprot entity CRYAA_HUMAN there are 44 pathogenic changes around while only 1 benign (98%) in NM_000394.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43169133-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.34778 (below the threshold of 3.09). GenCC associations: The gene is linked to early-onset lamellar cataract, early-onset anterior polar cataract, total early-onset cataract, cataract - microcornea syndrome, early-onset nuclear cataract, cataract 9 multiple types.
• 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 rank	MANE	Protein	UniProt
CRYAA	NM_000394.4	c.35G>A	p.Arg12His	missense_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1
LOC107987300	XR_007067885.1	n.546+1903C>T		intron_variant	Intron 1 of 2

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251314 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 15678

American (AMR) AF: 0.00 AC: 0 AN: 34568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17730

East Asian (EAS) AF: 0.00 AC: 0 AN: 38200

South Asian (SAS) AF: 0.00 AC: 0 AN: 74882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3932

European-Non Finnish (NFE) AF: 0.0000157 AC: 11 AN: 701872

Other (OTH) AF: 0.00 AC: 0 AN: 40706

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

Jun 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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"). 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. -

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
PromoterAI		-0.0054	Neutral
Varity_R		0.40
gMVP		0.80
Mutation Taster		=49/51	disease causing

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;