NM_001267550.2:c.99991T>C

Variant names:

• chr2-178537118-A-G
• rs56061641
• NM_001267550.2:c.99991T>C

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.99991T>C​(p.Cys33331Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000213 in 1,613,332 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.00031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:13
• Conservation: PhyloP100: 3.73
• 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=0.01258117).
• BP6: Variant 2-178537118-A-G is Benign according to our data. Variant chr2-178537118-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47622.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000203 (296/1461128) while in subpopulation MID AF = 0.0133 (77/5768). AF 95% confidence interval is 0.0109. There are 4 homozygotes in GnomAdExome4. There are 155 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.99991T>C	p.Cys33331Arg	missense	Exon 356 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.95068T>C	p.Cys31690Arg	missense	Exon 306 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.92287T>C	p.Cys30763Arg	missense	Exon 305 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.99991T>C	p.Cys33331Arg	missense	Exon 356 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.99835T>C	p.Cys33279Arg	missense	Exon 354 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.99715T>C	p.Cys33239Arg	missense	Exon 354 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152086 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000271 AC: 67 AN: 247674 AF XY: 0.000298

Gnomad AFR exome AF: 0.000455

Gnomad AMR exome AF: 0.000611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.000998

GnomAD4 exome AF: 0.000203 AC: 296 AN: 1461128 Hom.: 4 Cov.: 32 AF XY: 0.000213 AC XY: 155 AN XY: 726830

African (AFR) AF: 0.000389 AC: 13 AN: 33460

American (AMR) AF: 0.000582 AC: 26 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86186

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.0133 AC: 77 AN: 5768

European-Non Finnish (NFE) AF: 0.000113 AC: 126 AN: 1111614

Other (OTH) AF: 0.000365 AC: 22 AN: 60342

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152204 Hom.: 1 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74422

African (AFR) AF: 0.000144 AC: 6 AN: 41532

American (AMR) AF: 0.00118 AC: 18 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68006

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000167 Hom.: 0

Bravo AF: 0.000344

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000257 AC: 31

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000357

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	5	not provided (8)
-	1	4	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	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	See cases (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.93
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.059
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N
PhyloP100		3.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.24
Sift	Benign	0.85	T
Polyphen		0.0010	B
Vest4		0.37
MVP		0.37
MPC		0.15
ClinPred		0.045	T
GERP RS		5.4
Mutation Taster		=38/62	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: rs56061641; hg19: chr2-179401845;