NM_001164507.2:c.23477A>G

Variant names:

• chr2-151506988-T-C
• rs143602832
• NM_001164507.2:c.23477A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001164507.2(NEB):​c.23477A>G​(p.Asn7826Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,606,856 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. N7826N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 2.36
• Publications: 0 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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008227259).
• BP6: Variant 2-151506988-T-C is Benign according to our data. Variant chr2-151506988-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450098.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00165 (252/152314) while in subpopulation AFR AF = 0.00582 (242/41576). AF 95% confidence interval is 0.00522. There are 2 homozygotes in GnomAd4. There are 132 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NEB	NM_001164507.2	MANE Plus Clinical	c.23477A>G	p.Asn7826Ser	missense	Exon 163 of 182	NP_001157979.2
	NEB	NM_001164508.2	MANE Select	c.23477A>G	p.Asn7826Ser	missense	Exon 163 of 182	NP_001157980.2
	NEB	NM_001271208.2		c.23582A>G	p.Asn7861Ser	missense	Exon 164 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.23477A>G	p.Asn7826Ser	missense	Exon 163 of 182	ENSP00000380505.3
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.23477A>G	p.Asn7826Ser	missense	Exon 163 of 182	ENSP00000416578.2
	NEB	ENST00000409198.5	TSL:5	c.18374A>G	p.Asn6125Ser	missense	Exon 136 of 150	ENSP00000386259.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000318 AC: 79 AN: 248636 AF XY: 0.000230

Gnomad AFR exome AF: 0.00465

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 222 AN: 1454542 Hom.: 0 Cov.: 28 AF XY: 0.000141 AC XY: 102 AN XY: 723980

African (AFR) AF: 0.00556 AC: 185 AN: 33282

American (AMR) AF: 0.000134 AC: 6 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39548

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52944

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5292

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1106524

Other (OTH) AF: 0.000399 AC: 24 AN: 60104

GnomAD4 genome AF: 0.00165 AC: 252 AN: 152314 Hom.: 2 Cov.: 32 AF XY: 0.00177 AC XY: 132 AN XY: 74478

African (AFR) AF: 0.00582 AC: 242 AN: 41576

American (AMR) AF: 0.000458 AC: 7 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000571 Hom.: 0

Bravo AF: 0.00163

ESP6500AA AF: 0.00743 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000406 AC: 49

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.4
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.13
Sift	Benign	0.067	T
Sift4G	Uncertain	0.013	D
Polyphen		0.013	B
Vest4		0.25
MVP		0.58
MPC		0.054
ClinPred		0.022	T
GERP RS		4.9
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.28
Mutation Taster		=84/16	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: rs143602832; hg19: chr2-152363502;