rs148849567

Variant names:

• chr2-178583056-C-T
• rs148849567
• NM_001267550.2:c.65747G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.65747G>A​(p.Arg21916Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,611,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21916W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:16
• Conservation: PhyloP100: 3.72
• Publications: 9 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007562548).
• BP6: Variant 2-178583056-C-T is Benign according to our data. Variant chr2-178583056-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47229.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00126 (191/152136) while in subpopulation AFR AF = 0.00407 (169/41538). AF 95% confidence interval is 0.00357. There are 0 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.65747G>A	p.Arg21916Gln	missense	Exon 313 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.60824G>A	p.Arg20275Gln	missense	Exon 263 of 313	NP_001243779.1
	TTN	NM_133378.4		c.58043G>A	p.Arg19348Gln	missense	Exon 262 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.65747G>A	p.Arg21916Gln	missense	Exon 313 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.65591G>A	p.Arg21864Gln	missense	Exon 311 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.65471G>A	p.Arg21824Gln	missense	Exon 311 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 191 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000322 AC: 79 AN: 245030 AF XY: 0.000256

Gnomad AFR exome AF: 0.00380

Gnomad AMR exome AF: 0.000351

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.000337

GnomAD4 exome AF: 0.000154 AC: 225 AN: 1458976 Hom.: 0 Cov.: 30 AF XY: 0.000134 AC XY: 97 AN XY: 725620

African (AFR) AF: 0.00428 AC: 143 AN: 33402

American (AMR) AF: 0.000562 AC: 25 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000306 AC: 34 AN: 1110416

Other (OTH) AF: 0.000282 AC: 17 AN: 60226

GnomAD4 genome AF: 0.00126 AC: 191 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74356

African (AFR) AF: 0.00407 AC: 169 AN: 41538

American (AMR) AF: 0.00105 AC: 16 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67966

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000355 Hom.: 0

Bravo AF: 0.00164

ESP6500AA AF: 0.00327 AC: 13

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000389 AC: 47

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Benign	0.95
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.17	N
PhyloP100		3.7
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.15
Sift	Benign	0.14	T
Polyphen		0.98	D
Vest4		0.47
MVP		0.16
MPC		0.22
ClinPred		0.020	T
GERP RS		5.8
Mutation Taster		=93/7	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: rs148849567; hg19: chr2-179447783; COSMIC: COSV59935344; COSMIC: COSV59935344;