rs72677242

Variant names:

• chr2-178614880-G-A
• rs72677242
• NM_001267550.2:c.48727C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178614880-G-A
• chr2-178614880-G-C
• chr2-178614880-G-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.48727C>T​(p.Pro16243Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00245 in 1,575,958 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. P16243T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (20 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:15
• Conservation: PhyloP100: 5.91
• Publications: 12 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=0.007853955).
• BP6: Variant 2-178614880-G-A is Benign according to our data. Variant chr2-178614880-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47024.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00311 (472/151976) while in subpopulation NFE AF = 0.00415 (282/67896). AF 95% confidence interval is 0.00375. There are 1 homozygotes in GnomAd4. There are 281 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 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.48727C>T	p.Pro16243Ser	missense	Exon 260 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.43804C>T	p.Pro14602Ser	missense	Exon 210 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.41023C>T	p.Pro13675Ser	missense	Exon 209 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.48727C>T	p.Pro16243Ser	missense	Exon 260 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.48571C>T	p.Pro16191Ser	missense	Exon 258 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.48451C>T	p.Pro16151Ser	missense	Exon 258 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 472 AN: 151858 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00415

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00337 AC: 649 AN: 192712 AF XY: 0.00337

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.000471

Gnomad ASJ exome AF: 0.00186

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00379

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.00238 AC: 3392 AN: 1423982 Hom.: 20 Cov.: 33 AF XY: 0.00251 AC XY: 1769 AN XY: 704774

African (AFR) AF: 0.0000304 AC: 1 AN: 32850

American (AMR) AF: 0.000519 AC: 20 AN: 38524

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 29 AN: 25504

East Asian (EAS) AF: 0.00 AC: 0 AN: 37954

South Asian (SAS) AF: 0.000563 AC: 46 AN: 81748

European-Finnish (FIN) AF: 0.0154 AC: 790 AN: 51320

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5704

European-Non Finnish (NFE) AF: 0.00219 AC: 2394 AN: 1091358

Other (OTH) AF: 0.00188 AC: 111 AN: 59020

GnomAD4 genome AF: 0.00311 AC: 472 AN: 151976 Hom.: 1 Cov.: 32 AF XY: 0.00378 AC XY: 281 AN XY: 74270

African (AFR) AF: 0.0000482 AC: 2 AN: 41526

American (AMR) AF: 0.000197 AC: 3 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4818

European-Finnish (FIN) AF: 0.0159 AC: 168 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00415 AC: 282 AN: 67896

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00348 Hom.: 6

Bravo AF: 0.00145

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000258 AC: 1

ESP6500EA AF: 0.00326 AC: 27

ExAC AF: 0.00284 AC: 340

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	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	Long QT syndrome (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	1	-	Tip-toe gait (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Benign	0.92
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.88	L
PhyloP100		5.9
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.20
Sift	Benign	0.34	T
Polyphen		0.31	B
Vest4		0.38
MVP		0.17
MPC		0.091
ClinPred		0.020	T
GERP RS		5.6
Mutation Taster		=93/7	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: rs72677242; hg19: chr2-179479607; COSMIC: COSV104640825; COSMIC: COSV104640825;