rs72648953

Variant names:

• chr2-178728776-G-T
• rs72648953
• NM_001267550.2:c.19150C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178728776-G-T
• chr2-178728776-G-A
• chr2-178728776-G-C

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.19150C>A​(p.Pro6384Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,594,088 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P6384P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (12 hom.)
• Consequence: TTN NM_001267550.2 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:20
• Conservation: PhyloP100: 8.12
• 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=0.008000225).
• BP6: Variant 2-178728776-G-T is Benign according to our data. Variant chr2-178728776-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46653.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00225 (343/152232) while in subpopulation EAS AF = 0.00503 (26/5166). AF 95% confidence interval is 0.00353. There are 1 homozygotes in GnomAd4. There are 184 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.19150C>A	p.Pro6384Thr	missense splice_region	Exon 66 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.18199C>A	p.Pro6067Thr	missense splice_region	Exon 64 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.15418C>A	p.Pro5140Thr	missense splice_region	Exon 63 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.19150C>A	p.Pro6384Thr	missense splice_region	Exon 66 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.19150C>A	p.Pro6384Thr	missense splice_region	Exon 66 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18874C>A	p.Pro6292Thr	missense splice_region	Exon 64 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152114 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00502

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00282

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00304 AC: 738 AN: 242524 AF XY: 0.00297

Gnomad AFR exome AF: 0.000260

Gnomad AMR exome AF: 0.000418

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00752

Gnomad FIN exome AF: 0.0106

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00297 AC: 4285 AN: 1441856 Hom.: 12 Cov.: 32 AF XY: 0.00288 AC XY: 2052 AN XY: 713460

African (AFR) AF: 0.000365 AC: 12 AN: 32866

American (AMR) AF: 0.000413 AC: 18 AN: 43588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25656

East Asian (EAS) AF: 0.00390 AC: 153 AN: 39238

South Asian (SAS) AF: 0.00109 AC: 92 AN: 84558

European-Finnish (FIN) AF: 0.0110 AC: 583 AN: 52964

Middle Eastern (MID) AF: 0.00158 AC: 9 AN: 5684

European-Non Finnish (NFE) AF: 0.00296 AC: 3255 AN: 1097920

Other (OTH) AF: 0.00274 AC: 163 AN: 59382

GnomAD4 genome AF: 0.00225 AC: 343 AN: 152232 Hom.: 1 Cov.: 33 AF XY: 0.00247 AC XY: 184 AN XY: 74410

African (AFR) AF: 0.000457 AC: 19 AN: 41568

American (AMR) AF: 0.000328 AC: 5 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00503 AC: 26 AN: 5166

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4816

European-Finnish (FIN) AF: 0.00877 AC: 93 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00282 AC: 192 AN: 68018

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

Alfa AF: 0.00251 Hom.: 5

Bravo AF: 0.00173

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.00219 AC: 18

ExAC AF: 0.00296 AC: 358

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	6	not provided (6)
-	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	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Benign	0.69
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0080	T
MetaSVM	Uncertain	-0.17	T
PhyloP100		8.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.40
Sift	Benign	0.048	D
Polyphen		1.0	D
Vest4		0.18
MVP		0.42
MPC		0.49
ClinPred		0.040	T
GERP RS		5.6
Mutation Taster		=34/66	disease causing

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: rs72648953; hg19: chr2-179593503; COSMIC: COSV60063043; COSMIC: COSV60063043;