chr1-150578448-T-C

Variant names:

• chr1-150578448-T-C
• rs34645101
• NM_021960.5:c.732A>G

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_021960.5(MCL1):​c.732A>G​(p.Lys244Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,614,144 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (102 hom.)
• Consequence: MCL1 NM_021960.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0300
• Publications: 7 publications found

Genes affected

MCL1 (HGNC:6943): (MCL1 apoptosis regulator, BCL2 family member) This gene encodes an anti-apoptotic protein, which is a member of the Bcl-2 family. Alternative splicing results in multiple transcript variants. The longest gene product (isoform 1) enhances cell survival by inhibiting apoptosis while the alternatively spliced shorter gene products (isoform 2 and isoform 3) promote apoptosis and are death-inducing. [provided by RefSeq, Oct 2010]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-150578448-T-C is Benign according to our data. Variant chr1-150578448-T-C is described in ClinVar as Benign. ClinVar VariationId is 770854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.03 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0107 (15571/1461866) while in subpopulation MID AF = 0.0258 (149/5768). AF 95% confidence interval is 0.0225. There are 102 homozygotes in GnomAdExome4. There are 7822 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1234 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021960.5. 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
	MCL1	NM_021960.5	MANE Select	c.732A>G	p.Lys244Lys	synonymous	Exon 2 of 3	NP_068779.1	Q07820-1
	MCL1	NM_001197320.2		c.273A>G	p.Lys91Lys	synonymous	Exon 3 of 4	NP_001184249.1	A0A087WT64
	MCL1	NM_182763.3		c.688+395A>G		intron	N/A	NP_877495.1	Q07820-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCL1	ENST00000369026.3	TSL:1 MANE Select	c.732A>G	p.Lys244Lys	synonymous	Exon 2 of 3	ENSP00000358022.2	Q07820-1
	MCL1	ENST00000620947.4	TSL:1	c.273A>G	p.Lys91Lys	synonymous	Exon 3 of 4	ENSP00000477624.1	A0A087WT64
	MCL1	ENST00000307940.3	TSL:1	c.688+395A>G		intron	N/A	ENSP00000309973.3	Q07820-2

Frequencies

GnomAD3 genomes AF: 0.00810 AC: 1233 AN: 152160 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.0438

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00900 AC: 2264 AN: 251462 AF XY: 0.00943

Gnomad AFR exome AF: 0.00178

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.0402

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00309

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.0109

GnomAD4 exome AF: 0.0107 AC: 15571 AN: 1461866 Hom.: 102 Cov.: 32 AF XY: 0.0108 AC XY: 7822 AN XY: 727232

African (AFR) AF: 0.00242 AC: 81 AN: 33480

American (AMR) AF: 0.00816 AC: 365 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0427 AC: 1115 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00772 AC: 666 AN: 86258

European-Finnish (FIN) AF: 0.00268 AC: 143 AN: 53414

Middle Eastern (MID) AF: 0.0258 AC: 149 AN: 5768

European-Non Finnish (NFE) AF: 0.0111 AC: 12324 AN: 1111992

Other (OTH) AF: 0.0120 AC: 727 AN: 60394

GnomAD4 genome AF: 0.00810 AC: 1234 AN: 152278 Hom.: 9 Cov.: 32 AF XY: 0.00788 AC XY: 587 AN XY: 74474

African (AFR) AF: 0.00217 AC: 90 AN: 41552

American (AMR) AF: 0.0107 AC: 163 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 152 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00745 AC: 36 AN: 4830

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0109 AC: 740 AN: 68020

Other (OTH) AF: 0.0118 AC: 25 AN: 2114

Alfa AF: 0.0111 Hom.: 14

Bravo AF: 0.00867

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0114

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	9.1
DANN	Benign	0.81
PhyloP100		0.030
Mutation Taster		=100/0	polymorphism

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: rs34645101; hg19: chr1-150550924; COSMIC: COSV100329531; COSMIC: COSV100329531;