2-178650756-G-C

Variant names:

• chr2-178650756-G-C
• rs72650066
• NM_001267550.2:c.39704C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.39704C>G​(p.Pro13235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00925 in 1,602,542 control chromosomes in the GnomAD database, including 522 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13235A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0092 (477 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 2.10
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003309399).
• BP6: Variant 2-178650756-G-C is Benign according to our data. Variant chr2-178650756-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

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.39704C>G	p.Pro13235Arg	missense	Exon 209 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.35183C>G	p.Pro11728Arg	missense	Exon 164 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.32402C>G	p.Pro10801Arg	missense	Exon 163 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.39704C>G	p.Pro13235Arg	missense	Exon 209 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.39704C>G	p.Pro13235Arg	missense	Exon 209 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.39428C>G	p.Pro13143Arg	missense	Exon 207 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00954 AC: 1451 AN: 152136 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00440

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0376

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.0184 AC: 4287 AN: 232612 AF XY: 0.0192

Gnomad AFR exome AF: 0.000918

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.122

Gnomad FIN exome AF: 0.0227

Gnomad NFE exome AF: 0.00335

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.00921 AC: 13359 AN: 1450288 Hom.: 477 Cov.: 31 AF XY: 0.0102 AC XY: 7341 AN XY: 720170

African (AFR) AF: 0.000992 AC: 33 AN: 33268

American (AMR) AF: 0.00207 AC: 90 AN: 43542

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 527 AN: 25800

East Asian (EAS) AF: 0.132 AC: 5190 AN: 39204

South Asian (SAS) AF: 0.0379 AC: 3174 AN: 83818

European-Finnish (FIN) AF: 0.0248 AC: 1307 AN: 52752

Middle Eastern (MID) AF: 0.0181 AC: 104 AN: 5750

European-Non Finnish (NFE) AF: 0.00189 AC: 2096 AN: 1106214

Other (OTH) AF: 0.0140 AC: 838 AN: 59940

GnomAD4 genome AF: 0.00958 AC: 1458 AN: 152254 Hom.: 45 Cov.: 32 AF XY: 0.0112 AC XY: 834 AN XY: 74440

African (AFR) AF: 0.00130 AC: 54 AN: 41562

American (AMR) AF: 0.00203 AC: 31 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 68 AN: 3470

East Asian (EAS) AF: 0.124 AC: 642 AN: 5164

South Asian (SAS) AF: 0.0377 AC: 182 AN: 4832

European-Finnish (FIN) AF: 0.0241 AC: 256 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 68012

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00721 Hom.: 39

Bravo AF: 0.00737

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00106 AC: 4

ESP6500EA AF: 0.00341 AC: 28

ExAC AF: 0.0174 AC: 2103

Asia WGS AF: 0.0740 AC: 255 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	4	not provided (4)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.90
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Benign	0.22	T
Polyphen		0.010	B
Vest4		0.088
MPC		0.091
ClinPred		0.0038	T
GERP RS		3.1
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs72650066; hg19: chr2-179515483; COSMIC: COSV59894969; COSMIC: COSV59894969;