rs1057522021

Variant names:

• chr2-151600569-C-T
• rs1057522021
• NM_001164507.2:c.13661G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001271208.2(NEB):​c.13661G>A​(p.Ser4554Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S4554S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: NEB NM_001271208.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -6.23
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05860445).
• BP6: Variant 2-151600569-C-T is Benign according to our data. Variant chr2-151600569-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 384646.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271208.2. 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.13661G>A	p.Ser4554Asn	missense	Exon 89 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.13661G>A	p.Ser4554Asn	missense	Exon 89 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.13661G>A	p.Ser4554Asn	missense	Exon 89 of 183	NP_001258137.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	ENST00000397345.8	TSL:5 MANE Select	c.13661G>A	p.Ser4554Asn	missense	Exon 89 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.13661G>A	p.Ser4554Asn	missense	Exon 89 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.11601+9240G>A		intron	N/A	ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.000108 AC: 1 AN: 9228 AF XY: 0.000192

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.017
DANN	Benign	0.37
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.1	T
PhyloP100		-6.2
PROVEAN	Benign	0.52	N
REVEL	Benign	0.019
Sift	Benign	0.12	T
Sift4G	Benign	0.36	T
Vest4		0.089
MutPred		0.37		Loss of helix (P = 0.0093)
MVP		0.055
MPC		0.12
ClinPred		0.063	T
GERP RS		-5.1
gMVP		0.0020
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: rs1057522021; hg19: chr2-152457083;