chr2-178662368-G-A

Variant names:

• chr2-178662368-G-A
• rs201474544
• NM_001267550.2:c.37009C>T

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.37009C>T​(p.Pro12337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0213 in 1,481,876 control chromosomes in the GnomAD database, including 5,485 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (217 hom., cov: 16)
  • Exomes 𝑓: 0.022 (5268 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.18
• 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]

LOC124906100 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039865673).
• BP6: Variant 2-178662368-G-A is Benign according to our data. Variant chr2-178662368-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220962.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 (1682/128260) while in subpopulation NFE AF = 0.0213 (1328/62218). AF 95% confidence interval is 0.0204. There are 217 homozygotes in GnomAd4. There are 733 alleles in the male GnomAd4 subpopulation. Median coverage is 16. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 217 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.37009C>T	p.Pro12337Ser	missense	Exon 177 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34354+598C>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31573+598C>T		intron	N/A	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.37009C>T	p.Pro12337Ser	missense	Exon 177 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.37009C>T	p.Pro12337Ser	missense	Exon 177 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.36733C>T	p.Pro12245Ser	missense	Exon 175 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1683 AN: 128186 Hom.: 217 Cov.: 16

Gnomad AFR AF: 0.00406

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.00429

Gnomad ASJ AF: 0.00771

Gnomad EAS AF: 0.000297

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.00802

Gnomad MID AF: 0.00690

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.0179 AC: 3602 AN: 201414 AF XY: 0.0183

Gnomad AFR exome AF: 0.00297

Gnomad AMR exome AF: 0.00256

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.000313

Gnomad FIN exome AF: 0.00983

Gnomad NFE exome AF: 0.0260

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.0220 AC: 29833 AN: 1353616 Hom.: 5268 Cov.: 31 AF XY: 0.0218 AC XY: 14650 AN XY: 672028

African (AFR) AF: 0.00273 AC: 83 AN: 30406

American (AMR) AF: 0.00325 AC: 126 AN: 38808

Ashkenazi Jewish (ASJ) AF: 0.0107 AC: 264 AN: 24608

East Asian (EAS) AF: 0.0000321 AC: 1 AN: 31144

South Asian (SAS) AF: 0.0227 AC: 1583 AN: 69734

European-Finnish (FIN) AF: 0.0114 AC: 415 AN: 36518

Middle Eastern (MID) AF: 0.0123 AC: 47 AN: 3836

European-Non Finnish (NFE) AF: 0.0247 AC: 26258 AN: 1062770

Other (OTH) AF: 0.0189 AC: 1056 AN: 55792

GnomAD4 genome AF: 0.0131 AC: 1682 AN: 128260 Hom.: 217 Cov.: 16 AF XY: 0.0119 AC XY: 733 AN XY: 61612

African (AFR) AF: 0.00405 AC: 135 AN: 33314

American (AMR) AF: 0.00429 AC: 50 AN: 11668

Ashkenazi Jewish (ASJ) AF: 0.00771 AC: 24 AN: 3114

East Asian (EAS) AF: 0.000297 AC: 1 AN: 3372

South Asian (SAS) AF: 0.0162 AC: 48 AN: 2972

European-Finnish (FIN) AF: 0.00802 AC: 72 AN: 8974

Middle Eastern (MID) AF: 0.00741 AC: 2 AN: 270

European-Non Finnish (NFE) AF: 0.0213 AC: 1328 AN: 62218

Other (OTH) AF: 0.00571 AC: 10 AN: 1752

Alfa AF: 0.0162 Hom.: 64

ExAC AF: 0.0194 AC: 2004

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	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	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.9
DANN	Benign	0.71
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0040	T
PhyloP100		-1.2
Vest4		0.042
GERP RS		3.3
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201474544; hg19: chr2-179527095;