NM_001267550.2:c.10700G>A

Variant names:

• chr2-178756776-C-T
• rs72955213
• NM_001267550.2:c.10700G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.10700G>A​(p.Ser3567Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,613,548 control chromosomes in the GnomAD database, including 305 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (30 hom., cov: 32)
  • Exomes 𝑓: 0.018 (275 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 1.35
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037531555).
• BP6: Variant 2-178756776-C-T is Benign according to our data. Variant chr2-178756776-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0131 (1998/152260) while in subpopulation NFE AF = 0.0201 (1366/68018). AF 95% confidence interval is 0.0192. There are 30 homozygotes in GnomAd4. There are 963 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 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.10700G>A	p.Ser3567Asn	missense	Exon 46 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_133437.4		c.10187G>A	p.Ser3396Asn	missense	Exon 44 of 192	NP_597681.4	A0A0A0MRA3
	TTN	NM_001256850.1		c.10303+2208G>A		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.10700G>A	p.Ser3567Asn	missense	Exon 46 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.10700G>A	p.Ser3567Asn	missense	Exon 46 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.10424G>A	p.Ser3475Asn	missense	Exon 44 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1999 AN: 152142 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.00328

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00891

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0263

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0138 AC: 3412 AN: 247748 AF XY: 0.0136

Gnomad AFR exome AF: 0.00298

Gnomad AMR exome AF: 0.00604

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0178 AC: 26040 AN: 1461288 Hom.: 275 Cov.: 33 AF XY: 0.0174 AC XY: 12649 AN XY: 726922

African (AFR) AF: 0.00227 AC: 76 AN: 33464

American (AMR) AF: 0.00615 AC: 275 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 338 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39658

South Asian (SAS) AF: 0.00342 AC: 295 AN: 86256

European-Finnish (FIN) AF: 0.0270 AC: 1439 AN: 53352

Middle Eastern (MID) AF: 0.0134 AC: 77 AN: 5766

European-Non Finnish (NFE) AF: 0.0203 AC: 22605 AN: 1111614

Other (OTH) AF: 0.0154 AC: 932 AN: 60356

GnomAD4 genome AF: 0.0131 AC: 1998 AN: 152260 Hom.: 30 Cov.: 32 AF XY: 0.0129 AC XY: 963 AN XY: 74432

African (AFR) AF: 0.00327 AC: 136 AN: 41568

American (AMR) AF: 0.00890 AC: 136 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4822

European-Finnish (FIN) AF: 0.0263 AC: 279 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0201 AC: 1366 AN: 68018

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.0183 Hom.: 93

Bravo AF: 0.0117

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.00212 AC: 8

ESP6500EA AF: 0.0176 AC: 145

ExAC AF: 0.0139 AC: 1684

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0187

EpiControl AF: 0.0193

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	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	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
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.91
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.3
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.075
Sift	Benign	0.46	T
Vest4		0.12
MPC		0.078
ClinPred		0.0068	T
GERP RS		3.2
Mutation Taster		=78/22	polymorphism (auto)

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: rs72955213; hg19: chr2-179621503;