rs397515623

Variant names:

• chr21-43169259-C-T
• rs397515623
• NM_000394.4:c.160C>T

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000394.4(CRYAA):​c.160C>T​(p.Arg54Cys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000642392: Experimental studies have shown that this variant affects the structure and function of the alpha-crystallin protein (PMID:22045060, 22347476, 22140512, 23379525, 25018622, 25694240, 28179137).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R54P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 10)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.33
• Publications: 35 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: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000642392: Experimental studies have shown that this variant affects the structure and function of the alpha-crystallin protein (PMID: 22045060, 22347476, 22140512, 23379525, 25018622, 25694240, 28179137).
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000394.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43169260-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2574040.
• 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 total early-onset cataract, cataract 9 multiple types, cataract - microcornea syndrome, early-onset anterior polar cataract, early-onset nuclear cataract, early-onset lamellar cataract.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 21-43169259-C-T is Pathogenic according to our data. Variant chr21-43169259-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 68457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000394.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAA	NM_000394.4	MANE Select	c.160C>T	p.Arg54Cys	missense	Exon 1 of 3	NP_000385.1	P02489

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAA	ENST00000291554.6	TSL:1 MANE Select	c.160C>T	p.Arg54Cys	missense	Exon 1 of 3	ENSP00000291554.2	P02489
	CRYAA	ENST00000482775.1	TSL:5	n.173C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 76832 Hom.: 0 Cov.: 10

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000408 AC: 3 AN: 735266 Hom.: 0 Cov.: 10 AF XY: 0.00000786 AC XY: 3 AN XY: 381470

African (AFR) AF: 0.00 AC: 0 AN: 16786

American (AMR) AF: 0.00 AC: 0 AN: 35386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18010

East Asian (EAS) AF: 0.00 AC: 0 AN: 37302

South Asian (SAS) AF: 0.00 AC: 0 AN: 71278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29780

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2888

European-Non Finnish (NFE) AF: 0.00000614 AC: 3 AN: 488372

Other (OTH) AF: 0.00 AC: 0 AN: 35464

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 76832 Hom.: 0 Cov.: 10 AF XY: 0.00 AC XY: 0 AN XY: 36966

African (AFR) AF: 0.00 AC: 0 AN: 18884

American (AMR) AF: 0.00 AC: 0 AN: 8252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1962

East Asian (EAS) AF: 0.00 AC: 0 AN: 3986

South Asian (SAS) AF: 0.00 AC: 0 AN: 2670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 168

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 34188

Other (OTH) AF: 0.00 AC: 0 AN: 912

Alfa AF: 0.000236 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Cataract 9 multiple types (4)
1	-	-	Developmental cataract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.79		Loss of phosphorylation at S51 (P = 0.0579)
MVP		0.98
MPC		1.4
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.078	Neutral
Varity_R		0.36
gMVP		0.79
Mutation Taster		=11/89	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

Other links and lift over

dbSNP: rs397515623; hg19: chr21-44589369; COSMIC: COSV52352876; COSMIC: COSV52352876;