NM_001164507.2:c.*212T>C

Variant names:

• chr2-151485548-A-G
• rs1061317
• NM_001164507.2:c.*212T>C

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.*212T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00868 in 416,600 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0077 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (23 hom.)
• Consequence: NEB NM_001164507.2 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.58
• 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]

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 (BayesDel_noAF=-0.88).
• BP6: Variant 2-151485548-A-G is Benign according to our data. Variant chr2-151485548-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 892683.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00767 (1169/152362) while in subpopulation NFE AF = 0.0102 (692/68026). AF 95% confidence interval is 0.00954. There are 10 homozygotes in GnomAd4. There are 589 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.*212T>C		3_prime_UTR	Exon 182 of 182	NP_001157979.2	P20929-3
	NEB	NM_001164508.2	MANE Select	c.*212T>C		3_prime_UTR	Exon 182 of 182	NP_001157980.2	P20929-2
	NEB	NM_001271208.2		c.*212T>C		3_prime_UTR	Exon 183 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.*212T>C		3_prime_UTR	Exon 182 of 182	ENSP00000380505.3	P20929-2
	NEB	ENST00000427231.7	TSL:5 MANE Plus Clinical	c.*212T>C		3_prime_UTR	Exon 182 of 182	ENSP00000416578.2	P20929-3
	NEB	ENST00000409198.5	TSL:5	c.*212T>C		3_prime_UTR	Exon 150 of 150	ENSP00000386259.1	P20929-4

Frequencies

GnomAD3 genomes AF: 0.00768 AC: 1169 AN: 152244 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.0207

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0264

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00926 AC: 2446 AN: 264238 Hom.: 23 Cov.: 4 AF XY: 0.00941 AC XY: 1268 AN XY: 134774

African (AFR) AF: 0.000982 AC: 8 AN: 8150

American (AMR) AF: 0.00206 AC: 19 AN: 9214

Ashkenazi Jewish (ASJ) AF: 0.0166 AC: 159 AN: 9560

East Asian (EAS) AF: 0.00 AC: 0 AN: 23700

South Asian (SAS) AF: 0.000850 AC: 5 AN: 5880

European-Finnish (FIN) AF: 0.0251 AC: 516 AN: 20584

Middle Eastern (MID) AF: 0.00150 AC: 2 AN: 1332

European-Non Finnish (NFE) AF: 0.00959 AC: 1617 AN: 168624

Other (OTH) AF: 0.00698 AC: 120 AN: 17194

GnomAD4 genome AF: 0.00767 AC: 1169 AN: 152362 Hom.: 10 Cov.: 32 AF XY: 0.00790 AC XY: 589 AN XY: 74512

African (AFR) AF: 0.00139 AC: 58 AN: 41590

American (AMR) AF: 0.00353 AC: 54 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0207 AC: 72 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0264 AC: 280 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0102 AC: 692 AN: 68026

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.0112 Hom.: 0

Bravo AF: 0.00510

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Nemaline myopathy 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.65
DANN	Benign	0.61
PhyloP100		-1.6
Mutation Taster		=100/0	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: rs1061317; hg19: chr2-152342062;