rs72648927

Variant names:

• chr2-178734940-G-C
• rs72648927
• NM_001267550.2:c.14984C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.14984C>G​(p.Pro4995Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00884 in 1,608,326 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts 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. P4995S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0072 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (90 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:31
• Conservation: PhyloP100: 5.77
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007749319).
• BP6: Variant 2-178734940-G-C is Benign according to our data. Variant chr2-178734940-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00718 (1094/152284) while in subpopulation NFE AF = 0.00963 (655/68020). AF 95% confidence interval is 0.00902. There are 7 homozygotes in GnomAd4. There are 574 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 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.14984C>G	p.Pro4995Arg	missense	Exon 51 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.14033C>G	p.Pro4678Arg	missense	Exon 49 of 313	NP_001243779.1
	TTN	NM_133378.4		c.11252C>G	p.Pro3751Arg	missense	Exon 48 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.14984C>G	p.Pro4995Arg	missense	Exon 51 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.14984C>G	p.Pro4995Arg	missense	Exon 51 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.14708C>G	p.Pro4903Arg	missense	Exon 49 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00719 AC: 1094 AN: 152166 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00964

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00796 AC: 1883 AN: 236562 AF XY: 0.00838

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00200

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.00916

Gnomad OTH exome AF: 0.00841

GnomAD4 exome AF: 0.00902 AC: 13128 AN: 1456042 Hom.: 90 Cov.: 31 AF XY: 0.00901 AC XY: 6522 AN XY: 723782

African (AFR) AF: 0.00132 AC: 44 AN: 33406

American (AMR) AF: 0.00236 AC: 103 AN: 43690

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 289 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00496 AC: 425 AN: 85714

European-Finnish (FIN) AF: 0.0251 AC: 1332 AN: 53084

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5754

European-Non Finnish (NFE) AF: 0.00939 AC: 10413 AN: 1108780

Other (OTH) AF: 0.00844 AC: 508 AN: 60184

GnomAD4 genome AF: 0.00718 AC: 1094 AN: 152284 Hom.: 7 Cov.: 33 AF XY: 0.00771 AC XY: 574 AN XY: 74466

African (AFR) AF: 0.00128 AC: 53 AN: 41552

American (AMR) AF: 0.00209 AC: 32 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4824

European-Finnish (FIN) AF: 0.0265 AC: 281 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00963 AC: 655 AN: 68020

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00870 Hom.: 7

Bravo AF: 0.00492

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00161 AC: 6

ESP6500EA AF: 0.00902 AC: 74

ExAC AF: 0.00740 AC: 892

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	6	not provided (6)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Dilated cardiomyopathy 1G (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;C1838244:Tibial muscular dystrophy;C1858763:Dilated cardiomyopathy 1G;C1861065:Hypertrophic cardiomyopathy 9;C1863599:Myopathy, myofibrillar, 9, with early respiratory failure;C2673677:Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Heart failure (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Benign	0.88
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0077	T
MetaSVM	Benign	-1.1	T
PhyloP100		5.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.19
Sift	Benign	0.33	T
Polyphen		0.67	P
Vest4		0.32
MVP		0.26
MPC		0.19
ClinPred		0.025	T
GERP RS		5.9
Mutation Taster		=68/32	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: rs72648927; hg19: chr2-179599667; COSMIC: COSV99045468; COSMIC: COSV99045468;