rs12998234

Variant names:

• chr2-151606686-C-T
• rs12998234
• NM_001164507.2:c.12667G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001164508.2(NEB):​c.12667G>A​(p.Ala4223Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A4223A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (5 hom., cov: 14)
  • Exomes 𝑓: 0.0018 (560 hom.)
  • Failed GnomAD Quality Control
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.999
• 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: G2P, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal dominant nebulin-related myopathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004699439).
• BP6: Variant 2-151606686-C-T is Benign according to our data. Variant chr2-151606686-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 227724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001164508.2. 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.12667G>A	p.Ala4223Thr	missense	Exon 84 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.12667G>A	p.Ala4223Thr	missense	Exon 84 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.12667G>A	p.Ala4223Thr	missense	Exon 84 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.12667G>A	p.Ala4223Thr	missense	Exon 84 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.12667G>A	p.Ala4223Thr	missense	Exon 84 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.11601+3123G>A		intron	N/A	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 232 AN: 96318 Hom.: 5 Cov.: 14

Gnomad AFR AF: 0.00447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0125

Gnomad SAS AF: 0.00159

Gnomad FIN AF: 0.000436

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000475

Gnomad OTH AF: 0.000799

GnomAD2 exomes AF: 0.00437 AC: 400 AN: 91562 AF XY: 0.00432

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.00143

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0373

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00308

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00184 AC: 1560 AN: 849434 Hom.: 560 Cov.: 26 AF XY: 0.00192 AC XY: 813 AN XY: 422800

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

African (AFR) AF: 0.00193 AC: 58 AN: 30114

American (AMR) AF: 0.000948 AC: 17 AN: 17924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19290

East Asian (EAS) AF: 0.0467 AC: 998 AN: 21372

South Asian (SAS) AF: 0.00146 AC: 93 AN: 63540

European-Finnish (FIN) AF: 0.00433 AC: 89 AN: 20558

Middle Eastern (MID) AF: 0.00145 AC: 4 AN: 2766

European-Non Finnish (NFE) AF: 0.000371 AC: 236 AN: 636188

Other (OTH) AF: 0.00172 AC: 65 AN: 37682

⚠️ 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 AF: 0.00241 AC: 232 AN: 96438 Hom.: 5 Cov.: 14 AF XY: 0.00247 AC XY: 114 AN XY: 46080

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

African (AFR) AF: 0.00445 AC: 162 AN: 36384

American (AMR) AF: 0.00103 AC: 7 AN: 6776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2584

East Asian (EAS) AF: 0.0125 AC: 37 AN: 2952

South Asian (SAS) AF: 0.00159 AC: 5 AN: 3142

European-Finnish (FIN) AF: 0.000436 AC: 2 AN: 4590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.000475 AC: 18 AN: 37890

Other (OTH) AF: 0.000784 AC: 1 AN: 1276

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00582 Hom.: 2

ExAC AF: 0.00229 AC: 35

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Nemaline myopathy 2 (2)
-	-	1	Nemaline myopathy 2;C5543431:Arthrogryposis multiplex congenita 6 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.2
DANN	Benign	0.77
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.1	T
PhyloP100		-1.0
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.045
Sift	Benign	0.40	T
Sift4G	Uncertain	0.032	D
Vest4		0.12
MutPred		0.58		Gain of methylation at K4218 (P = 0.072)
MVP		0.31
MPC		0.31
ClinPred		0.025	T
GERP RS		3.1
gMVP		0.00061
Mutation Taster		=99/1	polymorphism (auto)

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: rs12998234; hg19: chr2-152463200; COSMIC: COSV104384796;