21-43172104-CGC-TCT

Variant names:

• chr21-43172104-CGC-TCT
• NM_000394.4:c.346_348delCGCinsTCT
• CRYAA p.Arg116Ser

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1_Very_Strong PM1 PM5 PP2 PP3

The NM_000394.4(CRYAA):​c.346_348delCGCinsTCT​(p.Arg116Ser) variant causes a missense change involving the alteration of a conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.10
• Publications: 0 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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_000394.4 (CRYAA) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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 chr21-43172105-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 16960.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: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.346_348delCGCinsTCT	p.Arg116Ser	missense	N/A	NP_000385.1	P02489
	CRYAA	NM_001363766.1		c.235_237delCGCinsTCT	p.Arg79Ser	missense	N/A	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.346_348delCGCinsTCT	p.Arg116Ser	missense	N/A	ENSP00000291554.2	P02489
	CRYAA	ENST00000398133.5	TSL:3	c.286_288delCGCinsTCT	p.Arg96Ser	missense	N/A	ENSP00000381201.1	E7EWH7
	CRYAA	ENST00000398132.2	TSL:2	c.235_237delCGCinsTCT	p.Arg79Ser	missense	N/A	ENSP00000381200.1	A0A8C8KJZ9

Frequencies

GnomAD3 genomes Cov.: 0

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1

Splicing

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

hg19: chr21-44592214;