rs377422414

Variant names:

• chr2-178658147-A-G
• rs377422414
• NM_001267550.2:c.37722T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.37722T>C​(p.Val12574Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,575,242 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (37 hom., cov: 18)
  • Exomes 𝑓: 0.00086 (116 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.00800
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-178658147-A-G is Benign according to our data. Variant chr2-178658147-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.008 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00696 (996/143008) while in subpopulation AFR AF = 0.0258 (958/37156). AF 95% confidence interval is 0.0244. There are 37 homozygotes in GnomAd4. There are 473 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.37722T>C	p.Val12574Val	synonymous	Exon 186 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.34522+858T>C		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.31741+858T>C		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.37722T>C	p.Val12574Val	synonymous	Exon 186 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.37722T>C	p.Val12574Val	synonymous	Exon 186 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.37446T>C	p.Val12482Val	synonymous	Exon 184 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 994 AN: 142904 Hom.: 36 Cov.: 18

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

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: 0.0000151

Gnomad OTH AF: 0.00605

GnomAD2 exomes AF: 0.00257 AC: 519 AN: 202244 AF XY: 0.00182

Gnomad AFR exome AF: 0.0379

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000612

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.000859 AC: 1231 AN: 1432234 Hom.: 116 Cov.: 31 AF XY: 0.000737 AC XY: 525 AN XY: 712744

African (AFR) AF: 0.0313 AC: 1014 AN: 32392

American (AMR) AF: 0.00151 AC: 64 AN: 42328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000597 AC: 5 AN: 83784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37774

Middle Eastern (MID) AF: 0.000244 AC: 1 AN: 4098

European-Non Finnish (NFE) AF: 0.0000488 AC: 54 AN: 1106624

Other (OTH) AF: 0.00156 AC: 93 AN: 59632

GnomAD4 genome AF: 0.00696 AC: 996 AN: 143008 Hom.: 37 Cov.: 18 AF XY: 0.00681 AC XY: 473 AN XY: 69448

African (AFR) AF: 0.0258 AC: 958 AN: 37156

American (AMR) AF: 0.00184 AC: 25 AN: 13578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5006

South Asian (SAS) AF: 0.00 AC: 0 AN: 4336

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10060

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

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66430

Other (OTH) AF: 0.00599 AC: 12 AN: 2004

Alfa AF: 0.00407 Hom.: 5

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (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	not specified (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.0
DANN	Benign	0.88
PhyloP100		-0.0080
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs377422414; hg19: chr2-179522874;