rs72648960

Variant names:

• chr2-178724331-G-A
• rs72648960
• NM_001267550.2:c.21044C>T

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.21044C>T​(p.Ala7015Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,613,534 control chromosomes in the GnomAD database, including 485 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A7015A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0089 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0081 (447 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 0.757
• Publications: 11 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]

ENSG00000267784 (HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019120276).
• BP6: Variant 2-178724331-G-A is Benign according to our data. Variant chr2-178724331-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46680.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.21044C>T	p.Ala7015Val	missense	Exon 72 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.20093C>T	p.Ala6698Val	missense	Exon 70 of 313	NP_001243779.1
	TTN	NM_133378.4		c.17312C>T	p.Ala5771Val	missense	Exon 69 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.21044C>T	p.Ala7015Val	missense	Exon 72 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.21044C>T	p.Ala7015Val	missense	Exon 72 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.20768C>T	p.Ala6923Val	missense	Exon 70 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1354 AN: 152116 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.0257

Gnomad FIN AF: 0.0243

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.0165 AC: 4111 AN: 248662 AF XY: 0.0169

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.123

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.0146

GnomAD4 exome AF: 0.00814 AC: 11899 AN: 1461300 Hom.: 447 Cov.: 33 AF XY: 0.00879 AC XY: 6391 AN XY: 726918

African (AFR) AF: 0.00108 AC: 36 AN: 33444

American (AMR) AF: 0.00152 AC: 68 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 279 AN: 26118

East Asian (EAS) AF: 0.132 AC: 5217 AN: 39672

South Asian (SAS) AF: 0.0263 AC: 2265 AN: 86244

European-Finnish (FIN) AF: 0.0249 AC: 1331 AN: 53392

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5760

European-Non Finnish (NFE) AF: 0.00165 AC: 1833 AN: 1111638

Other (OTH) AF: 0.0128 AC: 775 AN: 60346

GnomAD4 genome AF: 0.00892 AC: 1358 AN: 152234 Hom.: 38 Cov.: 33 AF XY: 0.0104 AC XY: 771 AN XY: 74410

African (AFR) AF: 0.00168 AC: 70 AN: 41568

American (AMR) AF: 0.00190 AC: 29 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.124 AC: 639 AN: 5160

South Asian (SAS) AF: 0.0257 AC: 124 AN: 4818

European-Finnish (FIN) AF: 0.0243 AC: 258 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 67998

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00622 Hom.: 78

Bravo AF: 0.00686

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00157 AC: 6

ESP6500EA AF: 0.00315 AC: 26

ExAC AF: 0.0164 AC: 1983

Asia WGS AF: 0.0690 AC: 240 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.97
Eigen	Benign	0.070
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.76
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.24
Sift	Benign	0.074	T
Polyphen		0.096	B
Vest4		0.14
MPC		0.10
ClinPred		0.029	T
GERP RS		6.0
Mutation Taster		=87/13	polymorphism (auto)

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: rs72648960; hg19: chr2-179589058; COSMIC: COSV59894993;