chr21-43169126-G-C

Variant names:

• chr21-43169126-G-C
• rs74315440
• NM_000394.4:c.27G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The ENST00000291554.6(CRYAA):​c.27G>C​(p.Trp9Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000104 in 959,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: CRYAA ENST00000291554.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.11
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• cataract 9 multiple types

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• cataract - microcornea syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset anterior polar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset lamellar cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• total early-onset cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

LOC107987300 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to early-onset lamellar cataract, cataract - microcornea syndrome, early-onset nuclear cataract, early-onset anterior polar cataract, total early-onset cataract, cataract 9 multiple types.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000291554.6. 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
	CRYAA	NM_000394.4	MANE Select	c.27G>C	p.Trp9Cys	missense	Exon 1 of 3	NP_000385.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAA	ENST00000291554.6	TSL:1 MANE Select	c.27G>C	p.Trp9Cys	missense	Exon 1 of 3	ENSP00000291554.2
	CRYAA	ENST00000482775.1	TSL:5	n.40G>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251332 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000104 AC: 1 AN: 959616 Hom.: 0 Cov.: 27 AF XY: 0.00000208 AC XY: 1 AN XY: 481794

African (AFR) AF: 0.00 AC: 0 AN: 15404

American (AMR) AF: 0.00 AC: 0 AN: 34430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17654

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38154

South Asian (SAS) AF: 0.00 AC: 0 AN: 74718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3934

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 700622

Other (OTH) AF: 0.00 AC: 0 AN: 40510

GnomAD4 genome Cov.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.85		Gain of methylation at R12 (P = 0.0373)
MVP		0.95
MPC		1.5
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		0.029	Neutral
Varity_R		0.77
gMVP		0.95
Mutation Taster		=11/89	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

Other links and lift over

dbSNP: rs74315440; hg19: chr21-44589236;