Genetic Variant NEB:p.Ala56_Leu57insLeuAlaGlnProAla (chr2-151727817-T-TGCTGGCTGTGCCAGA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001164507.2(NEB):c.153_167dupTCTGGCACAGCCAGC(p.Ala56_Leu57insLeuAlaGlnProAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,604,630 control chromosomes in the GnomAD database, including 15 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A56A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00062 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 14 hom. )

Consequence

NEB
NM_001164507.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.768

Publications

0 publications found

Variant links:

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

NEB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001164507.2

BP6

Variant 2-151727817-T-TGCTGGCTGTGCCAGA is Benign according to our data. Variant chr2-151727817-T-TGCTGGCTGTGCCAGA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 419871.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000622 (92/147970) while in subpopulation SAS AF = 0.0116 (56/4826). AF 95% confidence interval is 0.00918. There are 1 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 14 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	NM_001164507.2	MANE Plus Clinical	c.153_167dupTCTGGCACAGCCAGC	p.Ala56_Leu57insLeuAlaGlnProAla	disruptive_inframe_insertion	Exon 5 of 182	NP_001157979.2
NEB	NM_001164508.2	MANE Select	c.153_167dupTCTGGCACAGCCAGC	p.Ala56_Leu57insLeuAlaGlnProAla	disruptive_inframe_insertion	Exon 5 of 182	NP_001157980.2
NEB	NM_001271208.2		c.153_167dupTCTGGCACAGCCAGC	p.Ala56_Leu57insLeuAlaGlnProAla	disruptive_inframe_insertion	Exon 5 of 183	NP_001258137.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NEB	ENST00000397345.8	TSL:5 MANE Select	c.153_167dupTCTGGCACAGCCAGC	p.Ala56_Leu57insLeuAlaGlnProAla	disruptive_inframe_insertion	Exon 5 of 182	ENSP00000380505.3
NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.153_167dupTCTGGCACAGCCAGC	p.Ala56_Leu57insLeuAlaGlnProAla	disruptive_inframe_insertion	Exon 5 of 182	ENSP00000416578.2
NEB	ENST00000409198.5	TSL:5	c.153_167dupTCTGGCACAGCCAGC	p.Ala56_Leu57insLeuAlaGlnProAla	disruptive_inframe_insertion	Exon 5 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes

AF:

0.000615

AC:

AN:

147858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000793

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000729

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000325

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00154

AC:

379

AN:

246372

AF XY:

0.00197

show subpopulations

Gnomad AFR exome

AF:

0.0000713

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000468

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.00119

AC:

1736

AN:

1456660

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1062

AN XY:

724714

show subpopulations

African (AFR)

AF:

0.0000622

AC:

AN:

32170

American (AMR)

AF:

0.000180

AC:

AN:

44538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0107

AC:

927

AN:

86234

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53254

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.000645

AC:

715

AN:

1108826

Other (OTH)

AF:

0.00120

AC:

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

178

267

356

445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000622

AC:

AN:

147970

Hom.:

Cov.:

AF XY:

0.000760

AC XY:

AN XY:

72390

show subpopulations

African (AFR)

AF:

0.0000791

AC:

AN:

37934

American (AMR)

AF:

0.000728

AC:

AN:

15100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0116

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000325

AC:

AN:

67692

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000304

Hom.:

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NEB: PM4, BS1, BS2

Sep 12, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 19, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 30, 2017

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nemaline myopathy 2

Benign:3

Jun 10, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 06, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.77

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over