2-151655264-A-C

Variant names:

• chr2-151655264-A-C
• rs10930723
• NM_001164507.2:c.6807+6T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000397345.8(NEB):​c.6807+6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,477,502 control chromosomes in the GnomAD database, including 44,208 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (9835 hom., cov: 32)
  • Exomes 𝑓: 0.20 (34373 hom.)
• Consequence: NEB ENST00000397345.8 splice_region, intron
• Scores: Splicing: ADA: 0.0001402
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.210
• Publications: 10 publications found

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]

NEB Gene-Disease associations (from GenCC):

• nemaline myopathy 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Ambry Genetics
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• intermediate nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• severe congenital nemaline myopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 2-151655264-A-C is Benign according to our data. Variant chr2-151655264-A-C is described in ClinVar as Benign. ClinVar VariationId is 129756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000397345.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.6807+6T>G		splice_region intron	N/A	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.6807+6T>G		splice_region intron	N/A	NP_001157980.2
	NEB	NM_001271208.2		c.6807+6T>G		splice_region intron	N/A	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.6807+6T>G		splice_region intron	N/A	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.6807+6T>G		splice_region intron	N/A	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.6807+6T>G		splice_region intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45449 AN: 151888 Hom.: 9781 Cov.: 32

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.249 AC: 55485 AN: 223232 AF XY: 0.245

Gnomad AFR exome AF: 0.602

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.602

Gnomad FIN exome AF: 0.140

Gnomad NFE exome AF: 0.163

Gnomad OTH exome AF: 0.221

GnomAD4 exome AF: 0.196 AC: 259257 AN: 1325496 Hom.: 34373 Cov.: 20 AF XY: 0.198 AC XY: 131765 AN XY: 663884

African (AFR) AF: 0.603 AC: 18150 AN: 30080

American (AMR) AF: 0.150 AC: 5971 AN: 39746

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6150 AN: 24504

East Asian (EAS) AF: 0.624 AC: 23977 AN: 38454

South Asian (SAS) AF: 0.341 AC: 26035 AN: 76432

European-Finnish (FIN) AF: 0.141 AC: 6920 AN: 49066

Middle Eastern (MID) AF: 0.228 AC: 1210 AN: 5304

European-Non Finnish (NFE) AF: 0.157 AC: 157672 AN: 1006502

Other (OTH) AF: 0.238 AC: 13172 AN: 55408

GnomAD4 genome AF: 0.300 AC: 45557 AN: 152006 Hom.: 9835 Cov.: 32 AF XY: 0.297 AC XY: 22083 AN XY: 74292

African (AFR) AF: 0.583 AC: 24155 AN: 41432

American (AMR) AF: 0.182 AC: 2779 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 895 AN: 3466

East Asian (EAS) AF: 0.609 AC: 3141 AN: 5158

South Asian (SAS) AF: 0.336 AC: 1619 AN: 4812

European-Finnish (FIN) AF: 0.131 AC: 1381 AN: 10570

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.158 AC: 10762 AN: 68012

Other (OTH) AF: 0.286 AC: 604 AN: 2110

Alfa AF: 0.207 Hom.: 2044

Bravo AF: 0.315

Asia WGS AF: 0.539 AC: 1867 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Nemaline myopathy 2 (4)
-	-	3	not provided (3)
-	-	1	Arthrogryposis multiplex congenita 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.54
PhyloP100		-0.21
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.064
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: rs10930723; hg19: chr2-152511778; COSMIC: COSV51458593;