rs146914780

Variant names:

• chr21-43169253-C-T
• rs146914780
• NM_000394.4:c.154C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1 PP2 BP4_Strong BP6

The NM_000394.4(CRYAA):​c.154C>T​(p.Leu52Phe) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (13 hom., cov: 10)
  • Exomes 𝑓: 0.0039 (562 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 4.42
• Publications: 6 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: Likely_benign. The variant received -2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000394.4
• 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 early-onset lamellar cataract, cataract - microcornea syndrome, early-onset nuclear cataract, early-onset anterior polar cataract, total early-onset cataract, cataract 9 multiple types.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01380384).
• BP6: Variant 21-43169253-C-T is Benign according to our data. Variant chr21-43169253-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 340096.

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.154C>T	p.Leu52Phe	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.154C>T	p.Leu52Phe	missense	Exon 1 of 3	ENSP00000291554.2	P02489
	CRYAA	ENST00000482775.1	TSL:5	n.167C>T		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 175 AN: 76954 Hom.: 13 Cov.: 10

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00267

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: 0.00391

Gnomad OTH AF: 0.00444

GnomAD2 exomes AF: 0.00140 AC: 348 AN: 248854 AF XY: 0.00145

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000521

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00131

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00385 AC: 2886 AN: 748996 Hom.: 562 Cov.: 10 AF XY: 0.00359 AC XY: 1394 AN XY: 388362

African (AFR) AF: 0.000707 AC: 12 AN: 16982

American (AMR) AF: 0.00176 AC: 63 AN: 35860

Ashkenazi Jewish (ASJ) AF: 0.000275 AC: 5 AN: 18180

East Asian (EAS) AF: 0.00 AC: 0 AN: 37600

South Asian (SAS) AF: 0.00 AC: 0 AN: 71892

European-Finnish (FIN) AF: 0.000199 AC: 6 AN: 30114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2992

European-Non Finnish (NFE) AF: 0.00539 AC: 2693 AN: 499362

Other (OTH) AF: 0.00297 AC: 107 AN: 36014

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00227 AC: 175 AN: 77056 Hom.: 13 Cov.: 10 AF XY: 0.00207 AC XY: 77 AN XY: 37138

African (AFR) AF: 0.000792 AC: 15 AN: 18942

American (AMR) AF: 0.00266 AC: 22 AN: 8272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1972

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 162

European-Non Finnish (NFE) AF: 0.00391 AC: 134 AN: 34298

Other (OTH) AF: 0.00432 AC: 4 AN: 926

Alfa AF: 0.00223 Hom.: 1

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00120 AC: 146

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00305

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.34	N
PhyloP100		4.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.28
Sift	Benign	0.26	T
Sift4G	Benign	0.48	T
Polyphen		0.0010	B
Vest4		0.27
MVP		0.47
MPC		0.43
ClinPred		0.028	T
GERP RS		4.9
PromoterAI		0.0061	Neutral
Varity_R		0.36
gMVP		0.58
Mutation Taster		=84/16	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

Other links and lift over

dbSNP: rs146914780; hg19: chr21-44589363;