NM_001267550.2:c.81472C>G

Variant names:

• chr2-178564660-G-C
• rs200771189
• NM_001267550.2:c.81472C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.81472C>G​(p.Pro27158Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,613,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 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 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00051 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 2.47
• Publications: 7 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.036707878).
• BP6: Variant 2-178564660-G-C is Benign according to our data. Variant chr2-178564660-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196066.

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.81472C>G	p.Pro27158Ala	missense	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.76549C>G	p.Pro25517Ala	missense	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.73768C>G	p.Pro24590Ala	missense	Exon 275 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.81472C>G	p.Pro27158Ala	missense	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.81316C>G	p.Pro27106Ala	missense	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.81196C>G	p.Pro27066Ala	missense	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152082 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000351 AC: 87 AN: 248182 AF XY: 0.000267

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.000597

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000513 AC: 750 AN: 1461280 Hom.: 1 Cov.: 37 AF XY: 0.000513 AC XY: 373 AN XY: 726930

African (AFR) AF: 0.000120 AC: 4 AN: 33450

American (AMR) AF: 0.000179 AC: 8 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.000600 AC: 32 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000621 AC: 690 AN: 1111700

Other (OTH) AF: 0.000265 AC: 16 AN: 60348

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152082 Hom.: 0 Cov.: 33 AF XY: 0.000579 AC XY: 43 AN XY: 74268

African (AFR) AF: 0.000217 AC: 9 AN: 41434

American (AMR) AF: 0.00144 AC: 22 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000663 Hom.: 0

Bravo AF: 0.000423

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000963 AC: 8

ExAC AF: 0.000306 AC: 37

EpiCase AF: 0.000273

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	9	not provided (11)
-	-	2	not specified (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.77
Eigen	Benign	-0.072
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.5
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.098
Sift	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.31
MVP		0.14
MPC		0.081
ClinPred		0.022	T
GERP RS		5.1
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: rs200771189; hg19: chr2-179429387; COSMIC: COSV60182981;