rs149001703

Variant names:

• chr2-178539675-T-C
• rs149001703
• NM_001267550.2:c.98390A>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.98390A>G​(p.Asn32797Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00595 in 1,613,684 control chromosomes in the GnomAD database, including 39 homozygotes. 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. N32797D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (34 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:24
• Conservation: PhyloP100: 4.87
• Publications: 12 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=0.004747838).
• BP6: Variant 2-178539675-T-C is Benign according to our data. Variant chr2-178539675-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47600.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00498 (758/152216) while in subpopulation AMR AF = 0.0141 (215/15286). AF 95% confidence interval is 0.0125. There are 5 homozygotes in GnomAd4. There are 375 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.98390A>G	p.Asn32797Ser	missense	Exon 352 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.93467A>G	p.Asn31156Ser	missense	Exon 302 of 313	NP_001243779.1
	TTN	NM_133378.4		c.90686A>G	p.Asn30229Ser	missense	Exon 301 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.98390A>G	p.Asn32797Ser	missense	Exon 352 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.98234A>G	p.Asn32745Ser	missense	Exon 350 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.98114A>G	p.Asn32705Ser	missense	Exon 350 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 757 AN: 152098 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00678

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00449 AC: 1113 AN: 248154 AF XY: 0.00459

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.00600

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000839

Gnomad NFE exome AF: 0.00712

Gnomad OTH exome AF: 0.00531

GnomAD4 exome AF: 0.00605 AC: 8843 AN: 1461468 Hom.: 34 Cov.: 33 AF XY: 0.00592 AC XY: 4305 AN XY: 727024

African (AFR) AF: 0.00117 AC: 39 AN: 33466

American (AMR) AF: 0.00633 AC: 283 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 30 AN: 26132

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39694

South Asian (SAS) AF: 0.00110 AC: 95 AN: 86258

European-Finnish (FIN) AF: 0.000901 AC: 48 AN: 53268

Middle Eastern (MID) AF: 0.0108 AC: 62 AN: 5766

European-Non Finnish (NFE) AF: 0.00715 AC: 7953 AN: 1111792

Other (OTH) AF: 0.00547 AC: 330 AN: 60374

GnomAD4 genome AF: 0.00498 AC: 758 AN: 152216 Hom.: 5 Cov.: 32 AF XY: 0.00504 AC XY: 375 AN XY: 74440

African (AFR) AF: 0.00118 AC: 49 AN: 41532

American (AMR) AF: 0.0141 AC: 215 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00679 AC: 462 AN: 68002

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00612 Hom.: 11

Bravo AF: 0.00555

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00649 AC: 25

ESP6500AA AF: 0.000970 AC: 4

ESP6500EA AF: 0.00811 AC: 68

ExAC AF: 0.00435 AC: 526

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00859

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	6	not provided (6)
-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Long QT syndrome (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	Benign	0.064
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Benign	0.94
Eigen	Benign	-0.23
Eigen_PC	Benign	0.071
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.2	N
PhyloP100		4.9
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.18
Sift	Benign	0.27	T
Polyphen		0.044	B
Vest4		0.37
MVP		0.14
MPC		0.074
ClinPred		0.036	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	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: rs149001703; hg19: chr2-179404402; COSMIC: COSV60398154; COSMIC: COSV60398154;