2-178722348-T-G

Variant names:

• chr2-178722348-T-G
• rs201065037
• NM_001267550.2:c.22439A>C

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.22439A>C​(p.Gln7480Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,613,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 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. Q7480Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3
• Conservation: PhyloP100: 1.78
• Publications: 3 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15889996).
• BP6: Variant 2-178722348-T-G is Benign according to our data. Variant chr2-178722348-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 203314.

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.22439A>C	p.Gln7480Pro	missense	Exon 77 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.21488A>C	p.Gln7163Pro	missense	Exon 75 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.18707A>C	p.Gln6236Pro	missense	Exon 74 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.22439A>C	p.Gln7480Pro	missense	Exon 77 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.22439A>C	p.Gln7480Pro	missense	Exon 77 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.22163A>C	p.Gln7388Pro	missense	Exon 75 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152118 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000158 AC: 39 AN: 247288 AF XY: 0.000134

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000323

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000242 AC: 353 AN: 1461094 Hom.: 0 Cov.: 32 AF XY: 0.000217 AC XY: 158 AN XY: 726810

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000224 AC: 1 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

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

European-Non Finnish (NFE) AF: 0.000307 AC: 341 AN: 1111534

Other (OTH) AF: 0.000166 AC: 10 AN: 60322

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152118 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74298

African (AFR) AF: 0.000121 AC: 5 AN: 41438

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

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000324 Hom.: 0

Bravo AF: 0.000223

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000489 AC: 4

ExAC AF: 0.000224 AC: 27

EpiCase AF: 0.000218

EpiControl AF: 0.000297

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	not provided (5)
-	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	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.92
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.55	T
PhyloP100		1.8
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.39
Sift	Benign	0.13	T
Polyphen		0.73	P
Vest4		0.39
MVP		0.41
MPC		0.20
ClinPred		0.075	T
GERP RS		6.2
Mutation Taster		=88/12	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: rs201065037; hg19: chr2-179587075;