21-43169161-G-A

Variant names:

• chr21-43169161-G-A
• rs397515626
• NM_000394.4:c.62G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000394.4(CRYAA):​c.62G>A​(p.Arg21Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 11)
  • Exomes 𝑓: 0.0000041 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.25

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: Pathogenic. The variant received 17 ACMG points.

• PM1: In a chain Alpha-crystallin A(1-168) (size 167) 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 chr21-43169160-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68460.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, 0.97
• PP5: Variant 21-43169161-G-A is Pathogenic according to our data. Variant chr21-43169161-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 68461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43169161-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRYAA	NM_000394.4	c.62G>A	p.Arg21Gln	missense_variant	Exon 1 of 3	ENST00000291554.6	NP_000385.1
LOC107987300	XR_007067885.1	n.546+1876C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRYAA	ENST00000291554.6	c.62G>A	p.Arg21Gln	missense_variant	Exon 1 of 3	1	NM_000394.4	ENSP00000291554.2
CRYAA	ENST00000482775.1	n.75G>A		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251304 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.000163

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000411 AC: 4 AN: 972414 Hom.: 2 Cov.: 21 AF XY: 0.00000408 AC XY: 2 AN XY: 489658

African (AFR) AF: 0.00 AC: 0 AN: 18056

American (AMR) AF: 0.00 AC: 0 AN: 36254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18512

East Asian (EAS) AF: 0.00 AC: 0 AN: 38614

South Asian (SAS) AF: 0.00 AC: 0 AN: 76632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4026

European-Non Finnish (NFE) AF: 0.00000568 AC: 4 AN: 703878

Other (OTH) AF: 0.00 AC: 0 AN: 41948

GnomAD4 genome Cov.: 11

Alfa AF: 0.0000398 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cataract 9 multiple types Pathogenic:3

Nov 17, 2020

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 21 of the CRYAA protein (p.Arg21Gln). This variant is present in population databases (rs397515626, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant early-onset cataracts (PMID: 23255486, 26867756). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 68461). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg21 amino acid residue in CRYAA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22045060, 22140512, 22347476, 23441109, 29386872). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.50
MutPred		0.96		Gain of catalytic residue at R21 (P = 0.2419);
MVP		0.96
MPC		1.3
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		-0.0070	Neutral
Varity_R		0.54
gMVP		0.87
Mutation Taster		=21/79	disease causing (ClinVar)

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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Other links and lift over

dbSNP: rs397515626; hg19: chr21-44589271;