rs113802426

Variant names:

• chr21-43172082-C-T
• rs113802426
• NM_000394.4:c.324C>T
• CRYAA p.Gly108Gly

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000394.4(CRYAA):​c.324C>T​(p.Gly108Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CRYAA NM_000394.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.968
• Publications: 1 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 21-43172082-C-T is Benign according to our data. Variant chr21-43172082-C-T is described in ClinVar as Benign. ClinVar VariationId is 534953.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.324C>T	p.Gly108Gly	synonymous	Exon 3 of 3	NP_000385.1	P02489
	CRYAA	NM_001363766.1		c.213C>T	p.Gly71Gly	synonymous	Exon 3 of 3	NP_001350695.1	A0A8C8KJZ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAA	ENST00000291554.6	TSL:1 MANE Select	c.324C>T	p.Gly108Gly	synonymous	Exon 3 of 3	ENSP00000291554.2	P02489
	CRYAA	ENST00000398133.5	TSL:3	c.264C>T	p.Gly88Gly	synonymous	Exon 3 of 3	ENSP00000381201.1	E7EWH7
	CRYAA	ENST00000398132.2	TSL:2	c.213C>T	p.Gly71Gly	synonymous	Exon 3 of 3	ENSP00000381200.1	A0A8C8KJZ9

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.000836 AC: 209 AN: 250146 AF XY: 0.000546

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000490

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.00145 Hom.: 0

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Cataract 9 multiple types (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		0.97
Mutation Taster		=99/1	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs113802426; hg19: chr21-44592192; COSMIC: COSV52353380;