rs397515625

Variant names:

• chr21-43169160-C-T
• rs397515625
• NM_000394.4:c.61C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43169160-C-T
• chr21-43169160-C-A

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.61C>T​(p.Arg21Trp) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001591353: This variant has been reported to affect CRYAA protein function (PMID:22045060, 22347476, 22140512)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000024 (1 hom., cov: 11)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.45
• Publications: 27 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: SCV001591353: This variant has been reported to affect CRYAA protein function (PMID: 22045060, 22347476, 22140512).; SCV001819270: Published functional studies demonstrate a damaging effect (Kore et al., 2012, Raju et al., 2011; Raju et al., 2012); SCV005360949: Functional studies have shown that this variant impacts the interaction with αB-Crystallin and causes increased protein aggregation (Raju et al. 2011. PubMed ID: 22140512; Raju et al. 2012. PubMed ID: 22347476).
• PM1: In a chain Alpha-crystallin A(1-162) (size 161) in uniprot entity CRYAA_HUMAN there are 12 pathogenic changes around while only 1 benign (92%) in NM_000394.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43169161-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 68461.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). 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, 0.993
• PP5: Variant 21-43169160-C-T is Pathogenic according to our data. Variant chr21-43169160-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 68460.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.61C>T	p.Arg21Trp	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.61C>T	p.Arg21Trp	missense	Exon 1 of 3	ENSP00000291554.2	P02489
	CRYAA	ENST00000482775.1	TSL:5	n.74C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0000241 AC: 2 AN: 82874 Hom.: 1 Cov.: 11

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000921

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251324 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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 974658 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 490606

African (AFR) AF: 0.00 AC: 0 AN: 18004

American (AMR) AF: 0.00 AC: 0 AN: 36268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18490

East Asian (EAS) AF: 0.00 AC: 0 AN: 38598

South Asian (SAS) AF: 0.00 AC: 0 AN: 76746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34480

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4038

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 706034

Other (OTH) AF: 0.00 AC: 0 AN: 42000

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000241 AC: 2 AN: 82874 Hom.: 1 Cov.: 11 AF XY: 0.0000494 AC XY: 2 AN XY: 40486

African (AFR) AF: 0.00 AC: 0 AN: 15962

American (AMR) AF: 0.00 AC: 0 AN: 9032

Ashkenazi Jewish (ASJ) AF: 0.000921 AC: 2 AN: 2172

East Asian (EAS) AF: 0.00 AC: 0 AN: 4636

South Asian (SAS) AF: 0.00 AC: 0 AN: 3540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 188

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39612

Other (OTH) AF: 0.00 AC: 0 AN: 1074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Cataract 9 multiple types (5)
2	-	-	not provided (2)
1	-	-	Cataract 9, multiple types, with microcornea (1)
1	-	-	CRYAA-related disorder (1)
1	-	-	Developmental cataract (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.96		Gain of catalytic residue at Q25 (P = 0.1572)
MVP		0.95
MPC		1.2
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.017	Neutral
Varity_R		0.66
gMVP		0.90
Mutation Taster		=5/95	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: rs397515625; hg19: chr21-44589270; COSMIC: COSV52352923; COSMIC: COSV52352923;