chr2-151617472-C-A

Variant names:

• chr2-151617472-C-A
• rs878924060
• NM_001164507.2:c.11077-4G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001164507.2(NEB):​c.11077-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (0 hom., cov: 21)
  • Exomes 𝑓: 0.032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164507.2 splice_region, intron
• Scores: Splicing: ADA: 0.000008029
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.17
• 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=-0.81).
• BP6: Variant 2-151617472-C-A is Benign according to our data. Variant chr2-151617472-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 283780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NEB	NM_001164507.2	c.11077-4G>T		splice_region_variant, intron_variant	Intron 74 of 181	ENST00000427231.7	NP_001157979.2
NEB	NM_001164508.2	c.11077-4G>T		splice_region_variant, intron_variant	Intron 74 of 181	ENST00000397345.8	NP_001157980.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NEB	ENST00000397345.8	c.11077-4G>T		splice_region_variant, intron_variant	Intron 74 of 181	5	NM_001164508.2	ENSP00000380505.3
NEB	ENST00000427231.7	c.11077-4G>T		splice_region_variant, intron_variant	Intron 74 of 181	5	NM_001164507.2	ENSP00000416578.2
NEB	ENST00000486320.1	n.14G>T		non_coding_transcript_exon_variant	Exon 1 of 2	2
NEB	ENST00000409198.5	c.10348-4G>T		splice_region_variant, intron_variant	Intron 71 of 149	5		ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 8919 AN: 89130 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.0568

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0433

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.0474

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.0873

GnomAD2 exomes AF: 0.113 AC: 4057 AN: 35788 AF XY: 0.117

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0870

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.0909

Gnomad FIN exome AF: 0.161

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.108

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0321 AC: 23078 AN: 719696 Hom.: 0 Cov.: 13 AF XY: 0.0346 AC XY: 12460 AN XY: 360516

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

African (AFR) AF: 0.0352 AC: 632 AN: 17970

American (AMR) AF: 0.0559 AC: 887 AN: 15856

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 625 AN: 13968

East Asian (EAS) AF: 0.0227 AC: 594 AN: 26120

South Asian (SAS) AF: 0.0749 AC: 2737 AN: 36566

European-Finnish (FIN) AF: 0.0279 AC: 687 AN: 24618

Middle Eastern (MID) AF: 0.0398 AC: 95 AN: 2384

European-Non Finnish (NFE) AF: 0.0288 AC: 15834 AN: 549514

Other (OTH) AF: 0.0302 AC: 987 AN: 32700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.100 AC: 8919 AN: 89094 Hom.: 0 Cov.: 21 AF XY: 0.0933 AC XY: 4026 AN XY: 43134

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

African (AFR) AF: 0.142 AC: 2762 AN: 19442

American (AMR) AF: 0.0568 AC: 596 AN: 10494

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 265 AN: 2070

East Asian (EAS) AF: 0.0436 AC: 151 AN: 3464

South Asian (SAS) AF: 0.0972 AC: 244 AN: 2510

European-Finnish (FIN) AF: 0.0402 AC: 213 AN: 5304

Middle Eastern (MID) AF: 0.0417 AC: 7 AN: 168

European-Non Finnish (NFE) AF: 0.103 AC: 4510 AN: 43798

Other (OTH) AF: 0.0882 AC: 111 AN: 1258

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Oct 13, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nemaline myopathy 2 Benign:2

Aug 29, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.3
DANN	Benign	0.55
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000080
dbscSNV1_RF	Benign	0.0
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: rs878924060; hg19: chr2-152473986; COSMIC: COSV51417991;