rs200992277

Variant names:

• chr2-178659026-G-A
• rs200992277
• NM_001267550.2:c.37432C>T

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.37432C>T​(p.Pro12478Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict 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. P12478L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (10 hom., cov: 12)
  • Exomes 𝑓: 0.0027 (47 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:14
• Conservation: PhyloP100: -0.131
• Publications: 5 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=0.0039824545).
• BP6: Variant 2-178659026-G-A is Benign according to our data. Variant chr2-178659026-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46915.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00268 (2006/748686) while in subpopulation SAS AF = 0.0214 (1135/53006). AF 95% confidence interval is 0.0204. There are 47 homozygotes in GnomAdExome4. There are 1314 alleles in the male GnomAdExome4 subpopulation. Median coverage is 10. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 47 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.37432C>T	p.Pro12478Ser	missense	Exon 182 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34501C>T	p.Pro11501Ser	missense	Exon 156 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31720C>T	p.Pro10574Ser	missense	Exon 155 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.37432C>T	p.Pro12478Ser	missense	Exon 182 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37432C>T	p.Pro12478Ser	missense	Exon 182 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.37156C>T	p.Pro12386Ser	missense	Exon 180 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 226 AN: 103886 Hom.: 9 Cov.: 12

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00238

Gnomad ASJ AF: 0.00112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00227

GnomAD2 exomes AF: 0.00284 AC: 147 AN: 51728 AF XY: 0.00328

Gnomad AFR exome AF: 0.000380

Gnomad AMR exome AF: 0.000918

Gnomad ASJ exome AF: 0.000762

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00161

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00268 AC: 2006 AN: 748686 Hom.: 47 Cov.: 10 AF XY: 0.00345 AC XY: 1314 AN XY: 380958

African (AFR) AF: 0.000364 AC: 7 AN: 19242

American (AMR) AF: 0.000878 AC: 19 AN: 21630

Ashkenazi Jewish (ASJ) AF: 0.000875 AC: 14 AN: 16008

East Asian (EAS) AF: 0.000180 AC: 6 AN: 33258

South Asian (SAS) AF: 0.0214 AC: 1135 AN: 53006

European-Finnish (FIN) AF: 0.0000663 AC: 3 AN: 45280

Middle Eastern (MID) AF: 0.00458 AC: 12 AN: 2618

European-Non Finnish (NFE) AF: 0.00135 AC: 705 AN: 521342

Other (OTH) AF: 0.00289 AC: 105 AN: 36302

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00220 AC: 229 AN: 103998 Hom.: 10 Cov.: 12 AF XY: 0.00260 AC XY: 128 AN XY: 49194

African (AFR) AF: 0.000240 AC: 7 AN: 29160

American (AMR) AF: 0.00238 AC: 23 AN: 9664

Ashkenazi Jewish (ASJ) AF: 0.00112 AC: 3 AN: 2686

East Asian (EAS) AF: 0.00 AC: 0 AN: 4176

South Asian (SAS) AF: 0.0313 AC: 91 AN: 2906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.00212 AC: 102 AN: 48170

Other (OTH) AF: 0.00223 AC: 3 AN: 1346

Alfa AF: 0.00134 Hom.: 1

Bravo AF: 0.00105

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	1	2	not provided (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	Dilated cardiomyopathy 1G (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	14
DANN	Benign	0.77
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.64	T
PhyloP100		-0.13
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.13
Sift	Benign	0.040	D
Polyphen		0.0	B
Vest4		0.18
MVP		0.24
MPC		0.10
ClinPred		0.018	T
GERP RS		1.0
Mutation Taster		=98/2	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: rs200992277; hg19: chr2-179523753; COSMIC: COSV60221579; COSMIC: COSV60221579;