chr2-178680256-C-G

Variant names:

• chr2-178680256-C-G
• rs72650040
• NM_001267550.2:c.33416G>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.33416G>C​(p.Arg11139Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,612,462 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/21 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 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: TTN NM_001267550.2 missense
• Scores: Splicing: ADA: 0.00004627
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15
• Conservation: PhyloP100: -0.307
• Publications: 13 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076809227).
• BP6: Variant 2-178680256-C-G is Benign according to our data. Variant chr2-178680256-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46888.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00151 (229/152114) while in subpopulation NFE AF = 0.00269 (183/67920). AF 95% confidence interval is 0.00237. There are 0 homozygotes in GnomAd4. There are 93 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.33416G>C	p.Arg11139Thr	missense	Exon 139 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.32465G>C	p.Arg10822Thr	missense	Exon 137 of 313	NP_001243779.1
	TTN	NM_133378.4		c.29684G>C	p.Arg9895Thr	missense	Exon 136 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.33416G>C	p.Arg11139Thr	missense	Exon 139 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.33416G>C	p.Arg11139Thr	missense	Exon 139 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.33140G>C	p.Arg11047Thr	missense	Exon 137 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00151 AC: 230 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00159 AC: 394 AN: 248220 AF XY: 0.00157

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.00214 AC: 3129 AN: 1460348 Hom.: 6 Cov.: 31 AF XY: 0.00212 AC XY: 1542 AN XY: 726416

African (AFR) AF: 0.000270 AC: 9 AN: 33362

American (AMR) AF: 0.00249 AC: 111 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.000361 AC: 31 AN: 85976

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53394

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.00255 AC: 2839 AN: 1111234

Other (OTH) AF: 0.00197 AC: 119 AN: 60312

GnomAD4 genome AF: 0.00151 AC: 229 AN: 152114 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74382

African (AFR) AF: 0.000313 AC: 13 AN: 41532

American (AMR) AF: 0.00144 AC: 22 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

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

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00269 AC: 183 AN: 67920

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00213 Hom.: 0

Bravo AF: 0.00163

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.00328 AC: 27

ExAC AF: 0.00149 AC: 180

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00235

EpiControl AF: 0.00243

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	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	Limb-girdle muscular dystrophy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.79
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.31
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.087
Sift	Benign	0.095	T
Polyphen		0.0	B
Vest4		0.29
MVP		0.18
MPC		0.13
ClinPred		0.0085	T
GERP RS		1.6
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.0
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: rs72650040; hg19: chr2-179544983; COSMIC: COSV60155847;