rs201767727

Variant names:

• chr2-151512812-A-G
• rs201767727
• NM_001164507.2:c.23267T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BS1 BS2_Supporting

The NM_001164508.2(NEB):​c.23267T>C​(p.Met7756Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00144 in 1,612,576 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 5.19
• Publications: 7 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]

RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Specifications for NEB are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072886944).
• BP6: Variant 2-151512812-A-G is Benign according to our data. Variant chr2-151512812-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 167328.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00147 (2151/1460284) while in subpopulation MID AF = 0.00416 (24/5764). AF 95% confidence interval is 0.00287. There are 4 homozygotes in GnomAdExome4. There are 1091 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.23267T>C	p.Met7756Thr	missense	Exon 161 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.23267T>C	p.Met7756Thr	missense	Exon 161 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.23372T>C	p.Met7791Thr	missense	Exon 162 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.23267T>C	p.Met7756Thr	missense	Exon 161 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23267T>C	p.Met7756Thr	missense	Exon 161 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.18164T>C	p.Met6055Thr	missense	Exon 134 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152174 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00170 AC: 422 AN: 248290 AF XY: 0.00179

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00249

GnomAD4 exome AF: 0.00147 AC: 2151 AN: 1460284 Hom.: 4 Cov.: 30 AF XY: 0.00150 AC XY: 1091 AN XY: 726478

African (AFR) AF: 0.000149 AC: 5 AN: 33456

American (AMR) AF: 0.000649 AC: 29 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 424 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00136 AC: 117 AN: 86034

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53384

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5764

European-Non Finnish (NFE) AF: 0.00128 AC: 1424 AN: 1110844

Other (OTH) AF: 0.00196 AC: 118 AN: 60330

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152292 Hom.: 1 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74492

African (AFR) AF: 0.000313 AC: 13 AN: 41568

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00176 Hom.: 3

Bravo AF: 0.00110

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000523 AC: 2

ESP6500EA AF: 0.00194 AC: 16

ExAC AF: 0.00158 AC: 191

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00143

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Nemaline myopathy 2 (4)
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	NEB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.043	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.22
Sift	Benign	0.27	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.67
MVP		0.54
MPC		0.33
ClinPred		0.035	T
GERP RS		5.7
Varity_R		0.46
gMVP		0.11
Mutation Taster		=51/49	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: rs201767727; hg19: chr2-152369326;