rs61735856

Variant names:

• chr21-43170573-G-A
• rs61735856
• NM_000394.4:c.246G>A
• CRYAA p.Pro82Pro

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000394.4(CRYAA):​c.246G>A​(p.Pro82Pro) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.87
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 21-43170573-G-A is Benign according to our data. Variant chr21-43170573-G-A is described in ClinVar as Benign. ClinVar VariationId is 340098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.87 with no splicing effect.

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.246G>A	p.Pro82Pro	synonymous	Exon 2 of 3	NP_000385.1	P02489
	CRYAA	NM_001363766.1		c.135G>A	p.Pro45Pro	synonymous	Exon 2 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.246G>A	p.Pro82Pro	synonymous	Exon 2 of 3	ENSP00000291554.2	P02489
	CRYAA	ENST00000398133.5	TSL:3	c.186G>A	p.Pro62Pro	synonymous	Exon 2 of 3	ENSP00000381201.1	E7EWH7
	CRYAA	ENST00000398132.2	TSL:2	c.135G>A	p.Pro45Pro	synonymous	Exon 2 of 3	ENSP00000381200.1	A0A8C8KJZ9

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00318 AC: 799 AN: 251074 AF XY: 0.00238

Gnomad AFR exome AF: 0.0424

Gnomad AMR exome AF: 0.00237

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000979

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 5906 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3108

African (AFR) AF: 0.00 AC: 0 AN: 192

American (AMR) AF: 0.00 AC: 0 AN: 1026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 86

East Asian (EAS) AF: 0.00 AC: 0 AN: 1476

South Asian (SAS) AF: 0.00 AC: 0 AN: 766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 78

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2088

Other (OTH) AF: 0.00 AC: 0 AN: 186

GnomAD4 genome Cov.: 0

Alfa AF: 0.00492 Hom.: 3

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

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	-0.59
CADD	Benign	0.28
DANN	Benign	0.91
PhyloP100		-4.9
PromoterAI		0.0011	Neutral
Mutation Taster		=97/3	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: rs61735856;

hg19: chr21-44590683;