NM_000394.4:c.50T>C

Variant names:

• chr21-43169149-T-C
• rs148704068
• NM_000394.4:c.50T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM1 PP2 BP4_Moderate

The NM_000394.4(CRYAA):​c.50T>C​(p.Phe17Ser) variant causes a missense change. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 11)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CRYAA NM_000394.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.11
• 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: 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: Uncertain_significance. The variant received 1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 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=0.18111494).

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.50T>C	p.Phe17Ser	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.50T>C	p.Phe17Ser	missense	Exon 1 of 3	ENSP00000291554.2	P02489
	CRYAA	ENST00000482775.1	TSL:5	n.63T>C		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD2 exomes AF: 0.000362 AC: 91 AN: 251364 AF XY: 0.000339

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000649

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.000977

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 981078 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 493014

African (AFR) AF: 0.00 AC: 0 AN: 17526

American (AMR) AF: 0.00 AC: 0 AN: 35924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18272

East Asian (EAS) AF: 0.00 AC: 0 AN: 38486

South Asian (SAS) AF: 0.00 AC: 0 AN: 76712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4042

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 713518

Other (OTH) AF: 0.00 AC: 0 AN: 41904

GnomAD4 genome Cov.: 11

Alfa AF: 0.000439 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.074
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.5	L
PhyloP100		5.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.048	D
Polyphen		0.0020	B
Vest4		0.37
MVP		0.77
MPC		0.79
ClinPred		0.046	T
GERP RS		4.9
PromoterAI		-0.013	Neutral
Varity_R		0.24
gMVP		0.82
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

Other links and lift over

dbSNP: rs148704068; hg19: chr21-44589259;