rs72648929

Variant names:

• chr2-178734746-C-G
• rs72648929
• NM_001267550.2:c.15178G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178734746-C-G
• chr2-178734746-C-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.15178G>C​(p.Val5060Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00318 in 1,613,234 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 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. V5060I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (18 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:22
• Conservation: PhyloP100: 6.17
• Publications: 16 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=0.0074189305).
• BP6: Variant 2-178734746-C-G is Benign according to our data. Variant chr2-178734746-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46599.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00235 (358/152276) while in subpopulation SAS AF = 0.00891 (43/4826). AF 95% confidence interval is 0.0068. There are 2 homozygotes in GnomAd4. There are 190 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.15178G>C	p.Val5060Leu	missense	Exon 51 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.14227G>C	p.Val4743Leu	missense	Exon 49 of 313	NP_001243779.1
	TTN	NM_133378.4		c.11446G>C	p.Val3816Leu	missense	Exon 48 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.15178G>C	p.Val5060Leu	missense	Exon 51 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.15178G>C	p.Val5060Leu	missense	Exon 51 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.14902G>C	p.Val4968Leu	missense	Exon 49 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152158 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00335 AC: 833 AN: 248534 AF XY: 0.00384

Gnomad AFR exome AF: 0.000259

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00886

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00172

Gnomad NFE exome AF: 0.00372

Gnomad OTH exome AF: 0.00365

GnomAD4 exome AF: 0.00326 AC: 4770 AN: 1460958 Hom.: 18 Cov.: 31 AF XY: 0.00343 AC XY: 2490 AN XY: 726666

African (AFR) AF: 0.000508 AC: 17 AN: 33456

American (AMR) AF: 0.000693 AC: 31 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00972 AC: 254 AN: 26124

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39680

South Asian (SAS) AF: 0.00843 AC: 727 AN: 86204

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53378

Middle Eastern (MID) AF: 0.00990 AC: 57 AN: 5760

European-Non Finnish (NFE) AF: 0.00307 AC: 3416 AN: 1111292

Other (OTH) AF: 0.00320 AC: 193 AN: 60356

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152276 Hom.: 2 Cov.: 33 AF XY: 0.00255 AC XY: 190 AN XY: 74458

African (AFR) AF: 0.000433 AC: 18 AN: 41580

American (AMR) AF: 0.000589 AC: 9 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00891 AC: 43 AN: 4826

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00335 AC: 228 AN: 68002

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00249 Hom.: 0

Bravo AF: 0.00205

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000534 AC: 2

ESP6500EA AF: 0.00376 AC: 31

ExAC AF: 0.00350 AC: 423

EpiCase AF: 0.00404

EpiControl AF: 0.00345

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	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	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	Supraventricular tachycardia (1)
-	-	1	Tibial muscular dystrophy (1)
1	-	-	Tip-toe gait (1)
-	-	1	TTN-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.45
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0074	T
MetaSVM	Benign	-0.60	T
PhyloP100		6.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.24
Sift	Benign	0.59	T
Polyphen		0.71	P
Vest4		0.15
MVP		0.37
MPC		0.19
ClinPred		0.043	T
GERP RS		5.7
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72648929; hg19: chr2-179599473;