rs369544339

Variant names:

• chr2-178729493-T-G
• rs369544339
• NM_001267550.2:c.18663A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178729493-T-G
• chr2-178729493-T-C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001267550.2(TTN):​c.18663A>C​(p.Glu6221Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E6221G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 0.814
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055708796).
• BP6: Variant 2-178729493-T-G is Benign according to our data. Variant chr2-178729493-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46642.

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.18663A>C	p.Glu6221Asp	missense	Exon 64 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.17712A>C	p.Glu5904Asp	missense	Exon 62 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.14931A>C	p.Glu4977Asp	missense	Exon 61 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.18663A>C	p.Glu6221Asp	missense	Exon 64 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.18663A>C	p.Glu6221Asp	missense	Exon 64 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18387A>C	p.Glu6129Asp	missense	Exon 62 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000926 AC: 23 AN: 248470 AF XY: 0.0000965

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000712

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000112 AC: 164 AN: 1461374 Hom.: 0 Cov.: 33 AF XY: 0.000114 AC XY: 83 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000671 AC: 3 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00153 AC: 40 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000936 AC: 104 AN: 1111650

Other (OTH) AF: 0.000232 AC: 14 AN: 60360

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74456

African (AFR) AF: 0.0000241 AC: 1 AN: 41566

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000243 AC: 2

ExAC AF: 0.0000993 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.81
Eigen	Benign	0.10
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.69	T
PhyloP100		0.81
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.15
Sift	Benign	0.34	T
Polyphen		0.92	P
Vest4		0.33
MutPred		0.39		Loss of loop (P = 0.1242)
MVP		0.25
MPC		0.20
ClinPred		0.090	T
GERP RS		2.2
Mutation Taster		=57/43	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: rs369544339; hg19: chr2-179594220; COSMIC: COSV60390876;