NM_001267550.2:c.21668G>A

Variant names:

• chr2-178723432-C-T
• rs138853909
• NM_001267550.2:c.21668G>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.21668G>A​(p.Arg7223His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,611,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/19 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. R7223C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00093 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:15
• Conservation: PhyloP100: -0.590
• Publications: 6 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]

ENSG00000267784 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.011094272).
• BP6: Variant 2-178723432-C-T is Benign according to our data. Variant chr2-178723432-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46688.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000933 (142/152226) while in subpopulation AFR AF = 0.00214 (89/41544). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.21668G>A	p.Arg7223His	missense	Exon 74 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.20717G>A	p.Arg6906His	missense	Exon 72 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.17936G>A	p.Arg5979His	missense	Exon 71 of 312	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.21668G>A	p.Arg7223His	missense	Exon 74 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.21668G>A	p.Arg7223His	missense	Exon 74 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.21392G>A	p.Arg7131His	missense	Exon 72 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000934 AC: 142 AN: 152108 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000543 AC: 134 AN: 246762 AF XY: 0.000419

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.000963

Gnomad ASJ exome AF: 0.00181

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.000474

Gnomad OTH exome AF: 0.00101

GnomAD4 exome AF: 0.000264 AC: 385 AN: 1459368 Hom.: 0 Cov.: 33 AF XY: 0.000245 AC XY: 178 AN XY: 725728

African (AFR) AF: 0.00186 AC: 62 AN: 33388

American (AMR) AF: 0.000853 AC: 38 AN: 44536

Ashkenazi Jewish (ASJ) AF: 0.00158 AC: 41 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39614

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85884

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53298

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5750

European-Non Finnish (NFE) AF: 0.000175 AC: 194 AN: 1110622

Other (OTH) AF: 0.000647 AC: 39 AN: 60256

GnomAD4 genome AF: 0.000933 AC: 142 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000954 AC XY: 71 AN XY: 74426

African (AFR) AF: 0.00214 AC: 89 AN: 41544

American (AMR) AF: 0.00131 AC: 20 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68004

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.0109 Hom.: 2267

Bravo AF: 0.00125

ESP6500AA AF: 0.00155 AC: 6

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.000513 AC: 62

EpiCase AF: 0.000437

EpiControl AF: 0.000773

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	5	not provided (7)
-	-	5	not specified (5)
-	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	-	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	0.059
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.87
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.59
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.069
Sift	Benign	0.23	T
Polyphen		0.0040	B
Vest4		0.30
MVP		0.15
MPC		0.10
ClinPred		0.0062	T
GERP RS		2.3
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs138853909; hg19: chr2-179588159; COSMIC: COSV60230147; COSMIC: COSV60230147;