rs147233841

chr16-21278144-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001376256.1(CRYM):c.108C>A(p.Ser36Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000491 in 1,551,168 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: CRYM NM_001376256.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.879

Genes affected

CRYM (HGNC:2418): (crystallin mu) Crystallins are separated into two classes: taxon-specific and ubiquitous. The former class is also called phylogenetically-restricted crystallins. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. This gene encodes a taxon-specific crystallin protein that binds NADPH and has sequence similarity to bacterial ornithine cyclodeaminases. The encoded protein does not perform a structural role in lens tissue, and instead it binds thyroid hormone for possible regulatory or developmental roles. Mutations in this gene have been associated with autosomal dominant non-syndromic deafness. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.071457565).
• BP6: Variant 16-21278144-G-T is Benign according to our data. Variant chr16-21278144-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178331.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.
• BS2: High AC in GnomAd at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRYM	NM_001376256.1	c.108C>A	p.Ser36Arg	missense_variant	1/8	ENST00000572914.2
CRYM	NM_001888.5	c.108C>A	p.Ser36Arg	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRYM	ENST00000572914.2	c.108C>A	p.Ser36Arg	missense_variant	1/8	2	NM_001376256.1	P1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000314 AC: 49 AN: 155968 Hom.: 0 AF XY: 0.000388 AC XY: 32 AN XY: 82424

Gnomad AFR exome AF: 0.000113

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.000469

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000873

Gnomad FIN exome AF: 0.0000695

Gnomad NFE exome AF: 0.000512

Gnomad OTH exome AF: 0.000453

GnomAD4 exome AF: 0.000512 AC: 716 AN: 1398910 Hom.: 1 Cov.: 32 AF XY: 0.000522 AC XY: 360 AN XY: 690224

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000363

Gnomad4 ASJ exome AF: 0.000596

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000593

Gnomad4 OTH exome AF: 0.000466

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74436

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000356 AC: 3

ExAC AF: 0.000137 AC: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 26, 2013	The Ser36Arg variant in CRYM has not been reported in individuals with hearing l oss, but has been identified in 0.03% (4/8420) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs147233841). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational analy ses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ser36Arg variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The variant is c onserved in chimp, dog, cat, cow and frog but not in mouse and chicken. In summa ry, additional data is needed to determine the clinical significance of this var iant. -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	CRYM: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2023	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 36 of the CRYM protein (p.Ser36Arg). This variant is present in population databases (rs147233841, gnomAD 0.05%). This missense change has been observed in individual(s) with deafness (PMID: 36056583). ClinVar contains an entry for this variant (Variation ID: 178331). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CRYM protein function with a negative predictive value of 80%. 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	Benign	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.48	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.071	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.035	N;N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.21	N;N;.
REVEL	Benign	0.27
Sift	Benign	0.51	T;T;.
Sift4G	Benign	0.56	T;T;.
Polyphen		0.0040	B;B;.
Vest4		0.16
MutPred		0.55		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.71
MPC		0.37
ClinPred		0.022	T
GERP RS		2.7
Varity_R		0.21
gMVP		0.71

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: rs147233841; hg19: chr16-21289465;