NM_001267550.2:c.20335A>T

Variant names:

• chr2-178725987-T-A
• rs149470241
• NM_001267550.2:c.20335A>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_001267550.2(TTN):​c.20335A>T​(p.Ser6779Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,603,862 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 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 0.00060 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:16
• Conservation: PhyloP100: 2.77
• Publications: 8 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07339355).
• BP6: Variant 2-178725987-T-A is Benign according to our data. Variant chr2-178725987-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46670.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00163 (2363/1451598) while in subpopulation NFE AF = 0.00208 (2299/1106278). AF 95% confidence interval is 0.00201. There are 3 homozygotes in GnomAdExome4. There are 1146 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.20335A>T	p.Ser6779Cys	missense	Exon 70 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.19384A>T	p.Ser6462Cys	missense	Exon 68 of 313	NP_001243779.1
	TTN	NM_133378.4		c.16603A>T	p.Ser5535Cys	missense	Exon 67 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.20335A>T	p.Ser6779Cys	missense	Exon 70 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.20335A>T	p.Ser6779Cys	missense	Exon 70 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.20059A>T	p.Ser6687Cys	missense	Exon 68 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000598 AC: 91 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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: 0.00107

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000588 AC: 142 AN: 241612 AF XY: 0.000595

Gnomad AFR exome AF: 0.000332

Gnomad AMR exome AF: 0.0000920

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.00163 AC: 2363 AN: 1451598 Hom.: 3 Cov.: 31 AF XY: 0.00159 AC XY: 1146 AN XY: 721142

African (AFR) AF: 0.000272 AC: 9 AN: 33058

American (AMR) AF: 0.0000685 AC: 3 AN: 43806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39300

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84402

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00208 AC: 2299 AN: 1106278

Other (OTH) AF: 0.000800 AC: 48 AN: 59968

GnomAD4 genome AF: 0.000598 AC: 91 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74444

African (AFR) AF: 0.000361 AC: 15 AN: 41576

American (AMR) AF: 0.000196 AC: 3 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68006

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

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000623

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000269 AC: 1

ESP6500EA AF: 0.000487 AC: 4

ExAC AF: 0.000580 AC: 70

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	8	not provided (11)
-	-	3	not specified (3)
-	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	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.86
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.073	T
MetaSVM	Uncertain	-0.073	T
PhyloP100		2.8
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.50
Sift	Benign	0.033	D
Polyphen		0.99	D
Vest4		0.26
MVP		0.56
MPC		0.37
ClinPred		0.046	T
GERP RS		4.7
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: rs149470241; hg19: chr2-179590714;