rs14133

Variant names:

• chr11-111911973-G-C
• rs14133
• ENST00000526180.6:c.-224-25C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-111911973-G-C
• chr11-111911973-G-A
• chr11-111911973-G-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001885.3(CRYAB):​c.-198-51C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 509,026 control chromosomes in the GnomAD database, including 19,715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5628 hom., cov: 31)
  • Exomes 𝑓: 0.28 (14087 hom.)
• Consequence: CRYAB NM_001885.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.67
• Publications: 23 publications found

Genes affected

CRYAB (HGNC:2389): (crystallin alpha B) 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. 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. Elevated expression of alpha-B crystallin occurs in many neurological diseases; a missense mutation cosegregated in a family with a desmin-related myopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2019]

HSPB2 (HGNC:5247): (heat shock protein family B (small) member 2) The protein encoded by this gene belongs to the superfamily of small heat-shock proteins containing a conservative alpha-crystallin domain at the C-terminal part of the molecule. The protein is expressed preferentially in the heart and skeletal muscle. This protein regulates Myotonic Dystrophy Protein Kinase, which plays an important role in maintenance of muscle structure and function. [provided by RefSeq, Dec 2012]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-111911973-G-C is Benign according to our data. Variant chr11-111911973-G-C is described in ClinVar as Benign. ClinVar VariationId is 680264.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001885.3. 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
	CRYAB	NM_001289807.1		c.-198-51C>G		intron	N/A	NP_001276736.1	P02511
	CRYAB	NM_001368245.1		c.-198-51C>G		intron	N/A	NP_001355174.1	P02511
	CRYAB	NM_001885.3		c.-198-51C>G		intron	N/A	NP_001876.1	P02511

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRYAB	ENST00000526180.6	TSL:1	c.-224-25C>G		intron	N/A	ENSP00000436051.1	P02511
	CRYAB	ENST00000227251.7	TSL:5	c.-148C>G		5_prime_UTR	Exon 1 of 4	ENSP00000227251.3	P02511
	CRYAB	ENST00000651164.1		c.-159C>G		5_prime_UTR	Exon 1 of 4	ENSP00000498735.1	P02511

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40580 AN: 151920 Hom.: 5630 Cov.: 31

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.256

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.303

GnomAD4 exome AF: 0.278 AC: 99208 AN: 356988 Hom.: 14087 Cov.: 0 AF XY: 0.277 AC XY: 52020 AN XY: 187512

African (AFR) AF: 0.223 AC: 2369 AN: 10620

American (AMR) AF: 0.320 AC: 5035 AN: 15710

Ashkenazi Jewish (ASJ) AF: 0.360 AC: 4084 AN: 11332

East Asian (EAS) AF: 0.188 AC: 4492 AN: 23856

South Asian (SAS) AF: 0.255 AC: 9938 AN: 38948

European-Finnish (FIN) AF: 0.249 AC: 5152 AN: 20702

Middle Eastern (MID) AF: 0.332 AC: 521 AN: 1570

European-Non Finnish (NFE) AF: 0.288 AC: 61562 AN: 213482

Other (OTH) AF: 0.292 AC: 6055 AN: 20768

GnomAD4 genome AF: 0.267 AC: 40582 AN: 152038 Hom.: 5628 Cov.: 31 AF XY: 0.267 AC XY: 19830 AN XY: 74322

African (AFR) AF: 0.220 AC: 9132 AN: 41470

American (AMR) AF: 0.341 AC: 5206 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1259 AN: 3468

East Asian (EAS) AF: 0.179 AC: 926 AN: 5164

South Asian (SAS) AF: 0.244 AC: 1175 AN: 4818

European-Finnish (FIN) AF: 0.256 AC: 2707 AN: 10578

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19299 AN: 67958

Other (OTH) AF: 0.300 AC: 633 AN: 2112

Alfa AF: 0.267 Hom.: 710

Bravo AF: 0.270

Asia WGS AF: 0.227 AC: 792 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Dilated cardiomyopathy 1II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.93
PhyloP100		2.7
PromoterAI		0.044	Neutral
Mutation Taster		=295/5	polymorphism (auto)

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: rs14133; hg19: chr11-111782697;