rs184412722

Variant names:

• chr2-178729332-T-C
• rs184412722
• NM_001267550.2:c.18824A>G

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.18824A>G​(p.Asn6275Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00223 in 1,612,842 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (47 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22
• Conservation: PhyloP100: 6.26
• Publications: 8 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=0.005814582).
• BP6: Variant 2-178729332-T-C is Benign according to our data. Variant chr2-178729332-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46646.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00183 (279/152276) while in subpopulation SAS AF = 0.0244 (118/4828). AF 95% confidence interval is 0.0209. There are 6 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.18824A>G	p.Asn6275Ser	missense	Exon 64 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.17873A>G	p.Asn5958Ser	missense	Exon 62 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.15092A>G	p.Asn5031Ser	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.18824A>G	p.Asn6275Ser	missense	Exon 64 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.18824A>G	p.Asn6275Ser	missense	Exon 64 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18548A>G	p.Asn6183Ser	missense	Exon 62 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152158 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00383 AC: 950 AN: 247794 AF XY: 0.00490

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.000899

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00184

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00227 AC: 3314 AN: 1460566 Hom.: 47 Cov.: 32 AF XY: 0.00291 AC XY: 2111 AN XY: 726384

African (AFR) AF: 0.000419 AC: 14 AN: 33434

American (AMR) AF: 0.000716 AC: 32 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.000843 AC: 22 AN: 26100

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39670

South Asian (SAS) AF: 0.0214 AC: 1847 AN: 86200

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53380

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5754

European-Non Finnish (NFE) AF: 0.00107 AC: 1185 AN: 1111024

Other (OTH) AF: 0.00297 AC: 179 AN: 60322

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152276 Hom.: 6 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74448

African (AFR) AF: 0.000241 AC: 10 AN: 41572

American (AMR) AF: 0.00183 AC: 28 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.0244 AC: 118 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00169 AC: 115 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00163 Hom.: 1

Bravo AF: 0.00105

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000530 AC: 2

ESP6500EA AF: 0.00194 AC: 16

ExAC AF: 0.00441 AC: 533

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.00267

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	6	not provided (7)
-	-	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	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.94
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.56	T
PhyloP100		6.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.29
Sift	Benign	0.075	T
Polyphen		0.36	B
Vest4		0.42
MVP		0.17
MPC		0.089
ClinPred		0.027	T
GERP RS		5.9
Mutation Taster		=48/52	disease causing

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: rs184412722; hg19: chr2-179594059;