NM_001267550.2:c.20341G>A

Variant names:

• chr2-178725981-C-T
• rs72648958
• NM_001267550.2:c.20341G>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.20341G>A​(p.Glu6781Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,607,984 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (7 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:14
• Conservation: PhyloP100: 2.49
• 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]

ENSG00000267784 (HGNC:):

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=0.038528413).
• BP6: Variant 2-178725981-C-T is Benign according to our data. Variant chr2-178725981-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46671.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00116 (177/152210) while in subpopulation NFE AF = 0.00219 (149/67998). AF 95% confidence interval is 0.0019. There are 1 homozygotes in GnomAd4. There are 86 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.20341G>A	p.Glu6781Lys	missense	Exon 70 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.19390G>A	p.Glu6464Lys	missense	Exon 68 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.16609G>A	p.Glu5537Lys	missense	Exon 67 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.20341G>A	p.Glu6781Lys	missense	Exon 70 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.20341G>A	p.Glu6781Lys	missense	Exon 70 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.20065G>A	p.Glu6689Lys	missense	Exon 68 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152092 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00101 AC: 248 AN: 245308 AF XY: 0.00104

Gnomad AFR exome AF: 0.000327

Gnomad AMR exome AF: 0.000268

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000421

Gnomad NFE exome AF: 0.00170

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00219 AC: 3193 AN: 1455774 Hom.: 7 Cov.: 31 AF XY: 0.00214 AC XY: 1549 AN XY: 723680

African (AFR) AF: 0.000361 AC: 12 AN: 33274

American (AMR) AF: 0.000226 AC: 10 AN: 44218

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39412

South Asian (SAS) AF: 0.00110 AC: 94 AN: 85144

European-Finnish (FIN) AF: 0.000582 AC: 31 AN: 53260

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5738

European-Non Finnish (NFE) AF: 0.00264 AC: 2932 AN: 1108594

Other (OTH) AF: 0.00178 AC: 107 AN: 60172

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152210 Hom.: 1 Cov.: 33 AF XY: 0.00116 AC XY: 86 AN XY: 74408

African (AFR) AF: 0.000457 AC: 19 AN: 41540

American (AMR) AF: 0.000196 AC: 3 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00159 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00146 AC: 12

ExAC AF: 0.00106 AC: 128

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	5	not provided (8)
-	2	4	not specified (6)
-	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	Cardiomyopathy (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Distal myopathy (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Limb-girdle muscular dystrophy (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.40	T
PhyloP100		2.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.32
Sift	Benign	0.69	T
Polyphen		0.95	P
Vest4		0.36
MVP		0.41
MPC		0.23
ClinPred		0.037	T
GERP RS		5.9
Mutation Taster		=80/20	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: rs72648958; hg19: chr2-179590708;