rs78226234

Positions:

• chr2-151644443-A-G
• chr2-151644443-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001164507.2(NEB):​c.7644+25T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,569,952 control chromosomes in the GnomAD database, including 343 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.018 (325 hom.)
• Consequence: NEB NM_001164507.2 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.733

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-151644443-A-G is Benign according to our data. Variant chr2-151644443-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-151644443-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0122 (1861/152296) while in subpopulation SAS AF= 0.0317 (153/4824). AF 95% confidence interval is 0.0276. There are 18 homozygotes in gnomad4. There are 876 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NEB	NM_001164507.2	c.7644+25T>C		intron_variant		ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.7644+25T>C		intron_variant		ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.7644+25T>C		intron_variant		5	NM_001164508.2	ENSP00000380505	P5
NEB	ENST00000427231.7	c.7644+25T>C		intron_variant		5	NM_001164507.2	ENSP00000416578	A2
NEB	ENST00000409198.5	c.7644+25T>C		intron_variant		5		ENSP00000386259

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1863 AN: 152178 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00367

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0117

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00675

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.0147 AC: 3655 AN: 247888 Hom.: 59 AF XY: 0.0159 AC XY: 2136 AN XY: 134452

Gnomad AFR exome AF: 0.00272

Gnomad AMR exome AF: 0.00831

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.00424

Gnomad SAS exome AF: 0.0348

Gnomad FIN exome AF: 0.00400

Gnomad NFE exome AF: 0.0178

Gnomad OTH exome AF: 0.0138

GnomAD4 exome AF: 0.0183 AC: 25969 AN: 1417656 Hom.: 325 Cov.: 27 AF XY: 0.0186 AC XY: 13157 AN XY: 707792

Gnomad4 AFR exome AF: 0.00284

Gnomad4 AMR exome AF: 0.00868

Gnomad4 ASJ exome AF: 0.00305

Gnomad4 EAS exome AF: 0.00449

Gnomad4 SAS exome AF: 0.0336

Gnomad4 FIN exome AF: 0.00553

Gnomad4 NFE exome AF: 0.0197

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0122 AC: 1861 AN: 152296 Hom.: 18 Cov.: 32 AF XY: 0.0118 AC XY: 876 AN XY: 74476

Gnomad4 AFR AF: 0.00366

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00677

Gnomad4 SAS AF: 0.0317

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.00521 Hom.: 0

Bravo AF: 0.0118

Asia WGS AF: 0.0260 AC: 92 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.033
DANN	Benign	0.43

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: rs78226234; hg19: chr2-152500957;