NM_001267550.2:c.69821G>A

Variant names:

• chr2-178576311-C-T
• rs201043950
• NM_001267550.2:c.69821G>A

Variant summary

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

The NM_001267550.2(TTN):​c.69821G>A​(p.Gly23274Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,575,634 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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. G23274S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:18
• Conservation: PhyloP100: 7.86
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06508699).
• BP6: Variant 2-178576311-C-T is Benign according to our data. Variant chr2-178576311-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47277.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00105 (160/152146) while in subpopulation NFE AF = 0.00191 (130/67986). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 76 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

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.69821G>A	p.Gly23274Asp	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.64898G>A	p.Gly21633Asp	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.62117G>A	p.Gly20706Asp	missense	Exon 275 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.69821G>A	p.Gly23274Asp	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.69665G>A	p.Gly23222Asp	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.69545G>A	p.Gly23182Asp	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152028 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00191

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.00118 AC: 249 AN: 210944 AF XY: 0.00125

Gnomad AFR exome AF: 0.000204

Gnomad AMR exome AF: 0.000503

Gnomad ASJ exome AF: 0.000429

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000967

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.000812

GnomAD4 exome AF: 0.00133 AC: 1899 AN: 1423488 Hom.: 6 Cov.: 36 AF XY: 0.00140 AC XY: 988 AN XY: 705252

African (AFR) AF: 0.000126 AC: 4 AN: 31632

American (AMR) AF: 0.000612 AC: 23 AN: 37556

Ashkenazi Jewish (ASJ) AF: 0.000592 AC: 14 AN: 23648

East Asian (EAS) AF: 0.00 AC: 0 AN: 39336

South Asian (SAS) AF: 0.000165 AC: 13 AN: 78674

European-Finnish (FIN) AF: 0.000928 AC: 48 AN: 51728

Middle Eastern (MID) AF: 0.000724 AC: 4 AN: 5522

European-Non Finnish (NFE) AF: 0.00158 AC: 1731 AN: 1096684

Other (OTH) AF: 0.00106 AC: 62 AN: 58708

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.00102 AC XY: 76 AN XY: 74360

African (AFR) AF: 0.000120 AC: 5 AN: 41538

American (AMR) AF: 0.000523 AC: 8 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 67986

Other (OTH) AF: 0.000475 AC: 1 AN: 2104

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00100

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00230 AC: 19

ExAC AF: 0.000985 AC: 119

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	9	not provided (10)
-	1	3	not specified (4)
-	1	1	Cardiovascular phenotype (2)
-	1	1	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	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	-	Brugada syndrome (1)
-	-	1	Cardiomyopathy (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.060
CADD	Benign	19
DANN	Benign	0.72
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.065	T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.45
MPC		0.53
ClinPred		0.088	T
GERP RS		5.9
Mutation Taster		=1/99	disease causing

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: rs201043950; hg19: chr2-179441038; COSMIC: COSV99045470; COSMIC: COSV99045470;