rs72648962

Variant names:

• chr2-178724269-C-T
• rs72648962
• NM_001267550.2:c.21106G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178724269-C-T
• chr2-178724269-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.21106G>A​(p.Asp7036Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00323 in 1,612,118 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D7036V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (61 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (66 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 3.77
• Publications: 5 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]

ENSG00000267784 (HGNC:):

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=0.0036107004).
• BP6: Variant 2-178724269-C-T is Benign according to our data. Variant chr2-178724269-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

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.21106G>A	p.Asp7036Asn	missense	Exon 72 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.20155G>A	p.Asp6719Asn	missense	Exon 70 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.17374G>A	p.Asp5792Asn	missense	Exon 69 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.21106G>A	p.Asp7036Asn	missense	Exon 72 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.21106G>A	p.Asp7036Asn	missense	Exon 72 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.20830G>A	p.Asp6944Asn	missense	Exon 70 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0158 AC: 2404 AN: 152184 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00431 AC: 1066 AN: 247296 AF XY: 0.00318

Gnomad AFR exome AF: 0.0538

Gnomad AMR exome AF: 0.00303

Gnomad ASJ exome AF: 0.00552

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000491

Gnomad OTH exome AF: 0.00268

GnomAD4 exome AF: 0.00192 AC: 2805 AN: 1459816 Hom.: 66 Cov.: 33 AF XY: 0.00166 AC XY: 1208 AN XY: 726008

African (AFR) AF: 0.0523 AC: 1745 AN: 33360

American (AMR) AF: 0.00366 AC: 163 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 180 AN: 26060

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

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5746

European-Non Finnish (NFE) AF: 0.000354 AC: 393 AN: 1110838

Other (OTH) AF: 0.00485 AC: 292 AN: 60266

GnomAD4 genome AF: 0.0158 AC: 2403 AN: 152302 Hom.: 61 Cov.: 33 AF XY: 0.0151 AC XY: 1124 AN XY: 74456

African (AFR) AF: 0.0530 AC: 2204 AN: 41574

American (AMR) AF: 0.00739 AC: 113 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68010

Other (OTH) AF: 0.0170 AC: 36 AN: 2116

Alfa AF: 0.00508 Hom.: 49

Bravo AF: 0.0182

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0462 AC: 177

ESP6500EA AF: 0.000485 AC: 4

ExAC AF: 0.00507 AC: 613

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000601

EpiControl AF: 0.000535

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Benign	0.81
Eigen	Benign	0.082
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.96	T
PhyloP100		3.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.54	T
Polyphen		0.32	B
Vest4		0.18
MVP		0.23
MPC		0.13
ClinPred		0.020	T
GERP RS		6.0
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72648962; hg19: chr2-179588996; COSMIC: COSV59880785;