rs727505352

Variant names:

• chr2-178578835-G-A
• rs727505352
• NM_001267550.2:c.68195C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178578835-G-A
• chr2-178578835-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.68195C>T​(p.Ser22732Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,611,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. S22732S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 9.94
• 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]

ENSG00000270574 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16807699).
• BP6: Variant 2-178578835-G-A is Benign according to our data. Variant chr2-178578835-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290366.

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.68195C>T	p.Ser22732Leu	missense	Exon 320 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.63272C>T	p.Ser21091Leu	missense	Exon 270 of 313	NP_001243779.1
	TTN	NM_133378.4		c.60491C>T	p.Ser20164Leu	missense	Exon 269 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.68195C>T	p.Ser22732Leu	missense	Exon 320 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.68039C>T	p.Ser22680Leu	missense	Exon 318 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.67919C>T	p.Ser22640Leu	missense	Exon 318 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.000150 AC: 37 AN: 247480 AF XY: 0.000104

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000962

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000384 AC: 56 AN: 1459478 Hom.: 0 Cov.: 33 AF XY: 0.0000317 AC XY: 23 AN XY: 725730

African (AFR) AF: 0.0000898 AC: 3 AN: 33404

American (AMR) AF: 0.000830 AC: 37 AN: 44592

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39612

South Asian (SAS) AF: 0.0000466 AC: 4 AN: 85894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110496

Other (OTH) AF: 0.0000664 AC: 4 AN: 60282

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74200

African (AFR) AF: 0.0000483 AC: 2 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000187 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000910 AC: 11

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	23
DANN	Benign	0.91
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.17	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.24
MutPred		0.64		Loss of disorder (P = 0.0222)
MVP		0.59
MPC		0.17
ClinPred		0.32	T
GERP RS		5.9
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs727505352; hg19: chr2-179443562; COSMIC: COSV59896018; COSMIC: COSV59896018;