rs72648228

Variant names:

• chr2-178557743-G-C
• rs72648228
• NM_001267550.2:c.87611C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178557743-G-C
• chr2-178557743-G-A
• chr2-178557743-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.87611C>G​(p.Thr29204Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T29204T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 2.72
• Publications: 4 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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010675371).
• BP6: Variant 2-178557743-G-C is Benign according to our data. Variant chr2-178557743-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202942.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000643 (94/1461640) while in subpopulation AFR AF = 0.00248 (83/33480). AF 95% confidence interval is 0.00205. There are 0 homozygotes in GnomAdExome4. There are 39 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

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.87611C>G	p.Thr29204Arg	missense	Exon 328 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.82688C>G	p.Thr27563Arg	missense	Exon 278 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.79907C>G	p.Thr26636Arg	missense	Exon 277 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.87611C>G	p.Thr29204Arg	missense	Exon 328 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.87455C>G	p.Thr29152Arg	missense	Exon 326 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.87335C>G	p.Thr29112Arg	missense	Exon 326 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 248992 AF XY: 0.000155

Gnomad AFR exome AF: 0.00245

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461640 Hom.: 0 Cov.: 33 AF XY: 0.0000536 AC XY: 39 AN XY: 727102

African (AFR) AF: 0.00248 AC: 83 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111826

Other (OTH) AF: 0.000133 AC: 8 AN: 60370

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74482

African (AFR) AF: 0.00176 AC: 73 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.000620

ESP6500AA AF: 0.00128 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000215 AC: 26

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	not provided (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	13
DANN	Benign	0.89
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.10
Sift	Benign	0.26	T
Polyphen		0.76	P
Vest4		0.47
MVP		0.31
MPC		0.19
ClinPred		0.098	T
GERP RS		3.8
Mutation Taster		=65/35	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: rs72648228; hg19: chr2-179422470;