rs35445420

Variant names:

• chr2-178548239-G-A
• rs35445420
• NM_001267550.2:c.93387C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178548239-G-A
• chr2-178548239-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001267550.2(TTN):​c.93387C>T​(p.Ser31129Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,613,804 control chromosomes in the GnomAD database, including 631 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (76 hom., cov: 32)
  • Exomes 𝑓: 0.025 (555 hom.)
• Consequence: TTN NM_001267550.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 0.0990
• Publications: 6 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 2-178548239-G-A is Benign according to our data. Variant chr2-178548239-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.099 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0208 (3159/152216) while in subpopulation NFE AF = 0.0304 (2066/68004). AF 95% confidence interval is 0.0293. There are 76 homozygotes in GnomAd4. There are 1491 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 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.93387C>T	p.Ser31129Ser	synonymous	Exon 339 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.88464C>T	p.Ser29488Ser	synonymous	Exon 289 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.85683C>T	p.Ser28561Ser	synonymous	Exon 288 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.93387C>T	p.Ser31129Ser	synonymous	Exon 339 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.93231C>T	p.Ser31077Ser	synonymous	Exon 337 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.93111C>T	p.Ser31037Ser	synonymous	Exon 337 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3157 AN: 152098 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0200 AC: 4967 AN: 248470 AF XY: 0.0202

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.00996

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0311

Gnomad OTH exome AF: 0.0226

GnomAD4 exome AF: 0.0250 AC: 36539 AN: 1461588 Hom.: 555 Cov.: 34 AF XY: 0.0245 AC XY: 17795 AN XY: 727074

African (AFR) AF: 0.00400 AC: 134 AN: 33470

American (AMR) AF: 0.0137 AC: 611 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0111 AC: 289 AN: 26132

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

South Asian (SAS) AF: 0.00463 AC: 399 AN: 86258

European-Finnish (FIN) AF: 0.0278 AC: 1485 AN: 53388

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5766

European-Non Finnish (NFE) AF: 0.0290 AC: 32274 AN: 1111792

Other (OTH) AF: 0.0207 AC: 1251 AN: 60370

GnomAD4 genome AF: 0.0208 AC: 3159 AN: 152216 Hom.: 76 Cov.: 32 AF XY: 0.0200 AC XY: 1491 AN XY: 74418

African (AFR) AF: 0.00460 AC: 191 AN: 41556

American (AMR) AF: 0.0168 AC: 257 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4818

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0304 AC: 2066 AN: 68004

Other (OTH) AF: 0.0189 AC: 40 AN: 2112

Alfa AF: 0.0242 Hom.: 34

Bravo AF: 0.0204

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0285

EpiControl AF: 0.0314

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	5	not provided (5)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.053
DANN	Benign	0.81
PhyloP100		0.099
Mutation Taster		=87/13	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: rs35445420; hg19: chr2-179412966;