NM_001164507.2:c.19455G>A

Variant names:

• chr2-151553999-C-T
• rs182847302
• NM_001164507.2:c.19455G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001164507.2(NEB):​c.19455G>A​(p.Lys6485Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,613,752 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0042 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (25 hom.)
• Consequence: NEB NM_001164507.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 1.38
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 2-151553999-C-T is Benign according to our data. Variant chr2-151553999-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95110.
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00418 (637/152218) while in subpopulation AMR AF = 0.00745 (114/15296). AF 95% confidence interval is 0.00634. There are 6 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164507.2. 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
	NEB	NM_001164507.2	MANE Plus Clinical	c.19455G>A	p.Lys6485Lys	synonymous	Exon 126 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.19455G>A	p.Lys6485Lys	synonymous	Exon 126 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.19455G>A	p.Lys6485Lys	synonymous	Exon 126 of 183	NP_001258137.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.19455G>A	p.Lys6485Lys	synonymous	Exon 126 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.19455G>A	p.Lys6485Lys	synonymous	Exon 126 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.14352G>A	p.Lys4784Lys	synonymous	Exon 99 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 637 AN: 152100 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00488

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00401 AC: 999 AN: 248902 AF XY: 0.00427

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.00406

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00402

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00426 AC: 6231 AN: 1461534 Hom.: 25 Cov.: 31 AF XY: 0.00426 AC XY: 3097 AN XY: 727054

African (AFR) AF: 0.000747 AC: 25 AN: 33476

American (AMR) AF: 0.00407 AC: 182 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00356 AC: 93 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.00175 AC: 151 AN: 86248

European-Finnish (FIN) AF: 0.0120 AC: 641 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.00444 AC: 4936 AN: 1111734

Other (OTH) AF: 0.00331 AC: 200 AN: 60366

GnomAD4 genome AF: 0.00418 AC: 637 AN: 152218 Hom.: 6 Cov.: 32 AF XY: 0.00476 AC XY: 354 AN XY: 74404

African (AFR) AF: 0.000939 AC: 39 AN: 41534

American (AMR) AF: 0.00745 AC: 114 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00488 AC: 332 AN: 68010

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00356 Hom.: 0

Bravo AF: 0.00304

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00362

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	2	Nemaline myopathy 2 (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	7.8
DANN	Benign	0.62
PhyloP100		1.4
Mutation Taster		=97/3	polymorphism

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: rs182847302; hg19: chr2-152410513;