2-151583609-T-C

Variant names:

• chr2-151583609-T-C
• rs45612241
• NM_001164507.2:c.15821A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001164507.2(NEB):​c.15821A>G​(p.Asn5274Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N5274I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 5)
  • Exomes 𝑓: 0.0000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08808878).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.15821A>G	p.Asn5274Ser	missense_variant	Exon 101 of 182	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.15821A>G	p.Asn5274Ser	missense_variant	Exon 101 of 182	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.15821A>G	p.Asn5274Ser	missense_variant	Exon 101 of 182	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.15821A>G	p.Asn5274Ser	missense_variant	Exon 101 of 182	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000413693.5	c.11A>G	p.Asn4Ser	missense_variant	Exon 1 of 74	5		ENSP00000410961.1
NEB	ENST00000409198.5	c.11602-7255A>G		intron_variant	Intron 78 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes Cov.: 5

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000264 AC: 1 AN: 378372 Hom.: 0 Cov.: 2 AF XY: 0.00000503 AC XY: 1 AN XY: 198936

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 11586

American (AMR) AF: 0.00 AC: 0 AN: 16462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12090

East Asian (EAS) AF: 0.0000440 AC: 1 AN: 22706

South Asian (SAS) AF: 0.00 AC: 0 AN: 39174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1718

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 228674

Other (OTH) AF: 0.00 AC: 0 AN: 22042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 5

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.67
DEOGEN2	Benign	0.0075	.;T;.;T;.;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.62	T;T;T;T;.;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.088	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PROVEAN	Benign	-0.82	N;.;N;N;.;.
REVEL	Benign	0.078
Sift	Benign	1.0	T;.;T;T;.;.
Sift4G	Uncertain	0.014	D;D;D;T;D;D
Vest4		0.16
MutPred		0.35		Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);.;Gain of disorder (P = 0.0447);Gain of disorder (P = 0.0447);
MVP		0.28
MPC		0.25
ClinPred		0.11	T
GERP RS		3.8
PromoterAI		-0.013	Neutral
gMVP		0.0021
Mutation Taster		=88/12	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: rs45612241; hg19: chr2-152440123;