chr21-43169149-T-C

Position:

• chr21-43169149-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1 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

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]

LOC107987300 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000394.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.18111494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYAA	NM_000394.4	c.50T>C	p.Phe17Ser	missense_variant	1/3	ENST00000291554.6
LOC107987300	XR_007067885.1	n.546+1888A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYAA	ENST00000291554.6	c.50T>C	p.Phe17Ser	missense_variant	1/3	1	NM_000394.4	P1
CRYAA	ENST00000482775.1	n.63T>C		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD3 exomes AF: 0.000362 AC: 91 AN: 251364 Hom.: 1 AF XY: 0.000339 AC XY: 46 AN XY: 135870

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 11

Alfa AF: 0.000380 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

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.50T>C (p.F17S) alteration is located in exon 1 (coding exon 1) of the CRYAA gene. This alteration results from a T to C substitution at nucleotide position 50, causing the phenylalanine (F) at amino acid position 17 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cataract 9 multiple types Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2023

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 17 of the CRYAA protein (p.Phe17Ser). This variant is present in population databases (rs148704068, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CRYAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 2514624). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.94	N;N
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
Varity_R		0.64
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs148704068; hg19: chr21-44589259;