chr2-178542755-G-A

Variant names:

• chr2-178542755-G-A
• rs202064385
• NM_001267550.2:c.97099C>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.97099C>T​(p.Arg32367Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000302 in 1,613,720 control chromosomes in the GnomAD database, including 2 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. R32367H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:10
• Conservation: PhyloP100: 6.80
• 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]

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=0.111677855).
• BP6: Variant 2-178542755-G-A is Benign according to our data. Variant chr2-178542755-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47579.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000296 (433/1461528) while in subpopulation SAS AF = 0.00201 (173/86250). AF 95% confidence interval is 0.00176. There are 2 homozygotes in GnomAdExome4. There are 275 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.97099C>T	p.Arg32367Cys	missense	Exon 348 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.92176C>T	p.Arg30726Cys	missense	Exon 298 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.89395C>T	p.Arg29799Cys	missense	Exon 297 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.97099C>T	p.Arg32367Cys	missense	Exon 348 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.96943C>T	p.Arg32315Cys	missense	Exon 346 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.96823C>T	p.Arg32275Cys	missense	Exon 346 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000442 AC: 110 AN: 248626 AF XY: 0.000549

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.000896

Gnomad EAS exome AF: 0.000779

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000196

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.000296 AC: 433 AN: 1461528 Hom.: 2 Cov.: 32 AF XY: 0.000378 AC XY: 275 AN XY: 727064

African (AFR) AF: 0.000149 AC: 5 AN: 33466

American (AMR) AF: 0.000313 AC: 14 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 43 AN: 26132

East Asian (EAS) AF: 0.000857 AC: 34 AN: 39694

South Asian (SAS) AF: 0.00201 AC: 173 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.000117 AC: 130 AN: 1111748

Other (OTH) AF: 0.000431 AC: 26 AN: 60364

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.000981 AC: 15 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5162

South Asian (SAS) AF: 0.00186 AC: 9 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68004

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.000314

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.000414 AC: 50

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	3	not provided (7)
-	1	3	not specified (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	-	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	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.8
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.79
MPC		0.54
ClinPred		0.096	T
GERP RS		5.7
Mutation Taster		=75/25	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: rs202064385; hg19: chr2-179407482; COSMIC: COSV60279961; COSMIC: COSV60279961;