rs78592085

Variant names:

• chr2-151490008-G-A
• rs78592085
• NM_001164507.2:c.25367C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001164508.2(NEB):​c.25367C>T​(p.Thr8456Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0025 in 1,612,568 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T8456T) has been classified as Likely benign. The gene NEB is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (7 hom.)
• Consequence: NEB NM_001164508.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: 9.01
• Publications: 9 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011208594).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00203 (309/152250) while in subpopulation AMR AF = 0.00543 (83/15298). AF 95% confidence interval is 0.00448. There are 3 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.25367C>T	p.Thr8456Met	missense	Exon 181 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.25367C>T	p.Thr8456Met	missense	Exon 181 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.25472C>T	p.Thr8491Met	missense	Exon 182 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.25367C>T	p.Thr8456Met	missense	Exon 181 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.25367C>T	p.Thr8456Met	missense	Exon 181 of 182	ENSP00000416578.2	P20929-3
	RIF1	ENST00000457745.1	TSL:1	n.480+3252G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152132 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00196 AC: 489 AN: 248872 AF XY: 0.00186

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00385

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.000556

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00255 AC: 3725 AN: 1460318 Hom.: 7 Cov.: 31 AF XY: 0.00248 AC XY: 1803 AN XY: 726530

African (AFR) AF: 0.000478 AC: 16 AN: 33450

American (AMR) AF: 0.00400 AC: 179 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26130

East Asian (EAS) AF: 0.00116 AC: 46 AN: 39682

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86204

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53394

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5764

European-Non Finnish (NFE) AF: 0.00294 AC: 3260 AN: 1110632

Other (OTH) AF: 0.00227 AC: 137 AN: 60342

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152250 Hom.: 3 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74452

African (AFR) AF: 0.000578 AC: 24 AN: 41548

American (AMR) AF: 0.00543 AC: 83 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00262 AC: 178 AN: 68006

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00258 Hom.: 3

Bravo AF: 0.00286

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000532 AC: 2

ESP6500EA AF: 0.00267 AC: 22

ExAC AF: 0.00176 AC: 213

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	2	2	Nemaline myopathy 2 (4)
-	2	1	not specified (3)
-	1	-	Muscle weakness;C0699743:Congenital muscular dystrophy (1)
-	-	1	NEB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.059	T
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.071	B
Vest4		0.54
MVP		0.47
MPC		0.34
ClinPred		0.035	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.39
Mutation Taster		=94/6	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: rs78592085; hg19: chr2-152346522;